Amino-tetrazole analogues and methods of use

ABSTRACT

A compound having Formula (I) or Formula (II) 
     
       
         
         
             
             
         
       
         
         
           
             is disclosed as an P2X 7  antagonist, wherein A, B, C, Y, Y, Z, m, v, R 1 , R 2 , R 3 , R 4 , and R 5 , are as defined in the description. Methods and compositions for treating disease or condition modulated by P2X 7  are also disclosed.

RELATED APPLICATION

This application is a continuation-in-part of pending U.S. applicationSer. No. 11/120,718 filed Apr. 29, 2005, hereby incorporated in itsentirety by reference, which claims priority to U.S. ProvisionalApplication Ser. No. 60/566,238 filed on Apr. 29, 2004.

TECHNICAL FIELD

This invention relates to substituted aminotetrazoles analogues that areantagonists of P2X₇ receptors, and to the use of such compounds fortreating conditions related to P2X₇ receptor activation.

BACKGROUND OF THE INVENTION

P2X receptors are ionotropic receptors activated by ATP. The importanceof P2X receptors in nociception is underscored by the variety of painstates in which this endogenous ligand can be released. Of the seven P2Xreceptors, the P2X₇ is distinguished by its ability to form a large poreupon prolonged or repeated agonist stimulation. It is partiallyactivated by saturating concentrations of ATP, whereas it is fullyactivated by the synthetic ATP analog benzoylbenzoic ATP (BzATP)(Bianchi et al., Eur. J. Pharmacol. Vol. 376, pages 127-138, 1999). TheP2X₇ receptor is expressed by presynaptic terminals in the central andperipheral nervous systems, antigen-presenting cells includingmacrophages, human epidermal Langerhans' cells, microglial cells and anumber of tumor cell lines of varying origin (Jacobson K A, et al.“Adenosine and Adenine Nucleotides: From Molecular Biology toIntegrative Physiology”. L. Belardinelli and A. Pelleg (eds.), Kluwer,Boston, pages 149-166, 1995).

On glial cells, the P2X₇ receptor has been shown to mediate release ofglutamate (Anderson C. et al. Drug Dev. Res. Vol. 50. page 92, 2000).Since glutamate is known to be involved in the neurotransmission ofpainful sensory signals, inhibition of P2X₇ may have therapeutic utilityin the treatment of various pain states. Furthermore, oxidized ATP(oATP), a nonselective and irreversible P2X₇ antagonist, was recentlyreported to possess peripherally-mediated antinociceptive properties ininflamed rats (Dell'Antonio et al. Neuroscience Lett. Vol. 327. pages87-90, 2002). Thus, P2X₇ antagonists may have utility in the treatmentof a variety of pain states.

Recent data also suggested a possible role for P2X₇ receptor activationin neuroinflammation and neurodegeneration (Collo G. et al.Neuropharmacology, Vol. 36, pages 1277-1283, 1997). In the centralnervous system, the P2X₇ receptor is predominately expressed bymicroglia, the resident macrophages of the brain. Recent studiesindicate a role of the P2X₇ receptor in the generation of superoxide inmicroglia, and upregulation of P2X₇ receptors around β-amyloid plaquesin a transgenic mouse model for Alzheimer's disease (Parvathenani etal., J. Biol. Chemistry, Vol. 278, pages 13300-13317, 2003) and inmultiple sclerosis lesions from autopsy brain sections (Narcisse et al.,Glia, Vol. 49, pages 245-258 (2005).

Thus, P2X₇ antagonists may have utility in the treatment ofneurodegenerative conditions including stroke and Alzheimer's disease.

Activation of the P2X₇ receptor on cells of the immune system(macrophages, mast cells and lymphocytes) leads to release ofinterleukin-1β (IL-1β), giant cell formation, degranulation, andL-selectin shedding. Compounds acting at the P2X₇ receptor may thereforehave utility in the treatment of various disease states and conditionssuch as rheumatoid arthritis, osteoarthritis, psoriasis, allergicdermatitis, asthma, chronic obstructive pulmonary disease, airwayshyper-responsiveness, septic shock, glomerulonephritis, irritable boweldisease, Crohn's disease, ulcerative colitis, atherosclerosis, growthand metastases of malignant cells, myoblastic leukaemia, diabetes,Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemicheart disease, stroke and varicose veins.

Neuropathic pain is another type of pain different from pain involvedwith inflammatory or neurodegenerative conditions. Neuropathic pain isassociated with any disorder affecting any segment of the nervoussystem. Common causes of neuropathic pain are, among others, alcoholism,amputation, cancer chemotherapy, diabetes, trigeminal neuralgia, HIVinfection, multiple sclerosis, shingles and spine surgery. One of themost dramatic examples of neuropathic pain is called “phantom limbsyndrome” which occurs when an arm or a leg have been removed, but thebrain still gets pain messages from the missing limb.

A recent study reported the localization of P2X₇ on presynapticterminals in the central and peripheral nervous systems (Deuchars et al.J. Neuroscience, Vol. 21, p 7143-7152, 2001) where its activation waslinked to release of the excitatory amino acid neurotransmitterglutamate. This finding indicates a role for the P2X₇ receptor in theprocess of neuronal synaptic transmission and therefore a potential rolefor P2X₇ antagonists as novel therapeutic tool to treat neuropathicpain.

Oxidized ATP (oATP), a nonselective and irreversible P2X₇ antagonist,was recently reported to possess peripherally mediated antinociceptiveproperties in inflamed rats (Dell'Antonio et al. Neuroscience Lett, Vol.327, pages 87-90, 2002).

Studies from mice lacking P2X₇ receptor resulted in absence ofinflammatory and neuropathic hypersensitivity to mechanical and thermalstimuli, indicating a link between a P2X₇ purinoceptor gene andinflammatory and neuropathic pain (Chessell et al., Pain, Vol 114, pages386-396 (2005)).

Antagonists to the P2X₇ receptor significantly improved functionalrecovery and decreased cell death in spinal cord injury (SCI) animalmodels. Rats with SCI were administered P2X₇ receptor irreversibleantagonists oATP and PPADS with a resulting decrease of histologicalinjury and improved recovery of motor function after the lesions (Wanget al., Nature Medicine Vol. 10, pages B21-B27, 2004).

In view of the above facts, there is a need for selective P2X₇antagonist that can be efficiently used in preventing, treating, orameliorating states as neuropathic pain, chronic inflammatory pain,inflammation and neurodegenerative conditions associated with severalprogressive CNS disorders, including, but not limited to, Alzheimer'sdisease, Parkinson's disease, depression, amyotrophic lateral sclerosis,Huntington's disease, dementia with Lewy bodies, multiple sclerosis aswell as diminished CNS function resulting from traumatic brain injury.

SUMMARY OF THE INVENTION

In its principal embodiment, the present invention discloses a compoundhaving Formula (I) or Formula (II),

or a therapeutically acceptable salt, solvate, prodrug, or salt of aprodrug thereof, in which

R² is phenyl or pyridyl, in which each R² is substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a),—N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(2b);

R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c);

R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

m is 0, 1, 2, or 3;

X and Y are independently selected from the group consisting of —H,—C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, and C₆-alkyl; or

X and Y together with the carbon atom to which they are attached form aring selected from the group consisting of cyclopropane, cyclobutane,cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, dioxolane, tetrahydropyran, piperidine, morpholine,thiomorpholine, and piperazine, each or which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a),—OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

Z is —H, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; or

Z and X together with the atoms to which they are attached form a ringselected from the group consisting of pyrrolidine, piperidine,morpholine, thiomorpholine, and piperazine;

R¹ is

-   -   proximal phenyl which is unfused or fused with a distal        cyclopentane, cyclohexane, cyclopentene, cyclohexene, dioxane,        dioxolane, naphthalene, benzene, furan, imidazole, isothiazole,        oxazole, isoxazole, pyrazine, pyrazole, pyridazine, pyridine,        pyrimidine, pyrrole, tetrahydrofuran, tetrahydrothiophene,        thiazole, thiophene, pyrrolidine, dioxolane, pyrazolidine,        pyran, piperidine, morpholine, thiomorpholine, oxazolidinone,        morpholinone, or piperazine ring, in which the proximal phenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a),        —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1d), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c);    -   proximal isoxazolyl, oxazolyl, pyrrolidinyl, pyridyl, thienyl,        pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, or        imidazopyridinyl, each of which is unfused or fused with a        distal cyclopentane, cyclohexane, cyclopentene, cyclohexene,        naphthalene, benzene, furan, imidazole, isothiazole, oxazole,        isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,        pyrrole, tetrahydrofuran, tetrahydrothiophene, thiazole,        thiophene, pyrrolidine, dioxolane, pyrazolidine, pyran,        piperidine, morpholine, thiomorpholine, or piperazine ring, in        which each of the proximal pyrrolidinyl, pyridyl, thienyl,        pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, pyrimidinyl, pyrazinyl, or imidazopyridinyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substitutents independently selected from the group consisting        of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); or    -   proximal bicyclo[2,2,1]heptyl, cyclopentyl, cyclohexyl,        cyclopentenyl, or cyclohexenyl, each of which is unfused or        fused with a distal cyclopentane, cyclohexane, cyclopentene,        cyclohexene, naphthalene, benzene, furan, imidazole,        isothiazole, oxazole, isoxazole, pyrazine, pyrazole, pyridazine,        pyridine, pyrimidine, pyrrole, imidazoline, tetrahydrofuran,        tetrahydrothiophene, thiazole, thiophene, pyrrolidine,        dioxolane, pyrazoline, pyrazolidine, pyran, piperidine,        morpholine, thiomorpholine, or piperazine ring, in which the        proximal cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        ═O, —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c);        -   adamantyl unsubstituted or substituted with one, two, three,            or four substituents independently selected from the group            consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1d),            —OR^(1d), —NHR^(1d), —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d),            —SO₂NH₂, —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d),            —COOH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂; or        -   2,3-dihydrospiroindene-1,4′-piperidinyl unsubstituted or            substituted with one, two, three, or four substituents            independently selected from the group consisting of —Cl, —F,            —Br, —I, —NO₂, —OH, —NH₂, —R^(1d), —OR^(1d), —NHR^(1d),            —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₂,            —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH,            —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂;

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1b);

R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and NHR^(1d);

R^(1c) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(1c) is unsubstituted or substituted with one, two, three,or four substituents independently selected from the group consisting of═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —NH₂, —OR^(1aa),—SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂, —C(O)R^(1aa), S(O)₂R^(1aa),S(O)₂NH₂, S(O)₂N(R^(1aa))₂, —C(O)NH₂, —C(O)N(H)(R^(1aa)),—C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h), —N(H)R^(1h)),—N(R^(1d))(R^(1h)) and —R^(1h);

R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1bb);

R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —NO₂, —CN, haloalkyl, haloalkoxy, —OH, —OR^(1d),—SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d),—C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h);

R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(1e) is a monocyclic or bicyclic ring selected from the groupconsisting of cycloalkyl, heterocycle, aryl and heteroaryl, wherein eachring is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂,—NHR^(1aa), and —N(R^(1aa))₂;

R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, —R^(1h), or R^(1g);

R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of R^(1h);

R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(1h) is unsubstituted or substituted with one or two orthree or four or five substituents independently selected from the groupconsisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂,—OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH,—C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂;

provided that when R¹ is proximal phenyl fused with a distal pyrrole,thiophene, furan, pyrazole, isoxazole, or isothiazole ring, the distalpyrrole, thiophene, furan, pyrazole, isoxazole, or isothiazole ring isnot substituted with —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, pyrrolidinyl, piperidyl, tetrahydropyridyl,pyrrolinyl, —C₁-alkyl substituted with pyrrolidinyl or piperidyl,—C₂-alkyl substituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d), —C₃-alkylsubstituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d), —C₄-alkyl substitutedwith —N(R^(1d))₂, —NH₂, or —NHR^(1d), —C₅-alkyl substituted with—N(R^(1d))₂, —NH₂, or —NHR^(1d), or —C₆-alkyl substituted with—N(R^(1d))₂, —NH₂, or —NHR^(1d);

and provided that when m is 0 and R² is phenyl, then R¹ is not proximalunfused phenyl;

A is N or CR⁶;

B is N or CR⁷;

E is N or CR⁸;

provided that only one of A, B and E is N;

R³ is —NH₂, —R^(3a), —OR^(3a), —NHR^(3a), —N(R^(3a))₂, —NHC(O)R^(3f),—N(R^(3d))C(O)R^(3f), —R^(3c), —OR^(3e), —SR^(3e), —NH(R^(3e)), or—N(R^(3d))(R^(3e));

R^(3a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(3b);

R^(3b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —NH₂,—CN, —OH, —OR^(3d), —R^(3c), —N(R^(3d))₂, and —NHR^(3d);

R^(3c) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(3c) is unsubstituted or substituted with one, two, three,or four substituents independently selected from the group consisting of—Cl, —F, —Br, —I, —OH, —R^(3aa), —NH₂—OR^(3aa), —SR^(3aa), —NHR^(3aa),and —N(R^(3aa))₂;

R^(3d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(3aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(3bb);

R^(3bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(3d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(3d))₂, and —NHR^(3d);

R^(3e) is a monocyclic or bicyclic ring selected from the groupconsisting of cycloalkyl, heterocycle, aryl and heteroaryl, in whicheach ring is unsubstituted or substituted with one, two, three, or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —OH, —R^(3aa), —NH₂, —OR^(3aa), —SR^(3aa), —NR^(3aa),and —N(R^(3aa))₂;

R^(3f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, or R^(3g);

R^(3g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of aryl and heteroaryl;

v is one, two, or three, and when v is two or three, R³ may be the sameor different;

R⁴ is —Cl, —F, —Br, —I, —NH₂, —R^(4a), —OR^(4a), —NHR^(4a), —N(R^(4a))₂,—CN, —SR^(4a), or —SO₂R^(4a);

R^(4a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(4b);

R^(4b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(4c), —N(R^(4c))₂, —CN, —SR^(4c), and —SO₂R^(4c);

R^(4c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁵ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(5a), —OR^(5a), —NHR^(5a),—N(R^(5a))₂, —CN, —SR^(5a) or —SO₂R^(5a);

R^(5a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(5b);

R^(5b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(5c), —N(R^(5c))₂, —CN, —SR^(5c), and —SO₂R^(5c);

R^(5c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁶ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(6a), —OR^(6a), —NHR^(6a),—N(R^(6a))₂, —CN, —SR^(6a), or —SO₂R^(6a);

R^(6a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(6b);

R^(6b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(6c), —N(R^(6c))₂, —CN, —SR^(6c), and —SO₂R^(6c);

R^(6c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁷ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(7a), —OR^(7a), —NR^(7a),—N(R^(7a))₂, —CN, —SR^(7a), or —SO₂R^(7a);

R^(7a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(7b);

R^(7b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(7c), —N(R^(7c))₂, —CN, —SR^(7c), and —SO₂R^(7c);

R^(7c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁸ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(8a), —OR^(8a), —NHR^(8a),—N(R^(8a))₂, —CN, —SR^(8a), or —SO₂R^(8a);

R^(8a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(8b);

R^(8b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(8c), —N(R^(8c))₂, —CN, —SR^(8c), and SO₂R^(8c);

R^(8c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; and

with the proviso that the following compounds are excluded:N-benzyl-1-(4-methoxyphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methylphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methoxyphenyl)-1H-tetrazol-5-amine; andN,1-bis(2,4-dimethylphenyl)-1H-tetrazol-5-amine.

Another embodiment of the present invention relates to a pharmaceuticalcomposition comprising a compound of the present invention, or atherapeutically acceptable salt, prodrug, solvate, salt of a prodrug, orcombination thereof, as defined hereinafter, in combination with apharmaceutically acceptable carrier. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regime for treatment or prevention of chronicinflammatory pain, neuropathic pain, spinal cord injury,neurodegeneration, or depression. The compositions may contain one ormore compounds of the present invention.

A further embodiment of the present invention provides a method fortreating or preventing rheumatoid arthritis, osteoarthritis, psoriasis,Crohn's disease, spinal cord injury, neurodegenerative disease,Alzheimer's disease, depression, chronic inflammatory pain andneuropathic pain. Accordingly, the present invention provides a compoundof formula (I) or (II), or a therapeutically acceptable salt, solvate,prodrug, salt of a prodrug, or combination thereof, as definedhereinafter, for use in the treatment or prevention of theabove-mentioned diseases.

Yet another embodiment of the present invention provides the use of acompound of Formula (I) or (II), or a therapeutically acceptable salt,solvate, prodrug, salt of a prodrug, or combination thereof, as definedhereafter, in the preparation of a medicament for the treatment orprevention of the aforementioned diseases.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides a compound havingFormula (I) or Formula (II),

or a therapeutically acceptable salt, solvate, prodrug, or salt of aprodrug thereof, in which

R² is phenyl or pyridyl, in which each R² is substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a),—N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(2b);

R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c);

R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

m is 0, 1, 2, or 3;

X and Y are independently selected from the group consisting of —H,—C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, and C₆-alkyl; or

X and Y together with the carbon atom to which they are attached form aring selected from the group consisting of cyclopropane, cyclobutane,cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, dioxolane, tetrahydropyran, piperidine, morpholine,thiomorpholine, and piperazine, each or which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a),—OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

Z is —H, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; or

Z and X together with the atoms to which they are attached form a ringselected from the group consisting of pyrrolidine, piperidine,morpholine, thiomorpholine, and piperazine;

R¹ is

-   -   proximal phenyl which is unfused or fused with a distal        cyclopentane, cyclohexane, cyclopentene, cyclohexene, dioxane,        dioxolane, naphthalene, benzene, furan, imidazole, isothiazole,        oxazole, isoxazole, pyrazine, pyrazole, pyridazine, pyridine,        pyrimidine, pyrrole, tetrahydrofuran, tetrahydrothiophene,        thiazole, thiophene, pyrrolidine, dioxolane, pyrazolidine,        pyran, piperidine, morpholine, thiomorpholine, oxazolidinone,        morpholinone, or piperazine ring, in which the proximal phenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a),        —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f) and —R^(1e);    -   proximal isoxazolyl, oxazolyl, pyrrolidinyl, pyridyl, thienyl,        pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, or        imidazopyridinyl, each of which is unfused or fused with a        distal cyclopentane, cyclohexane, cyclopentene, cyclohexene,        naphthalene, benzene, furan, imidazole, isothiazole, oxazole,        isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,        pyrrole, tetrahydrofuran, tetrahydrothiophene, thiazole,        thiophene, pyrrolidine, dioxolane, pyrazolidine, pyran,        piperidine, morpholine, thiomorpholine, or piperazine ring, in        which the proximal pyrrolidinyl, pyridyl, thienyl, pyrrolyl,        pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, pyrimidinyl, pyrazinyl, or imidazopyridinyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a),        —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1e); or    -   proximal bicyclo[2,2,1]heptyl, cyclopentyl, cyclohexyl,        cyclopentenyl, or cyclohexenyl, each of which is unfused or        fused with a distal cyclopentane, cyclohexane, cyclopentene,        cyclohexene, naphthalene, benzene, furan, imidazole,        isothiazole, oxazole, isoxazole, pyrazine, pyrazole, pyridazine,        pyridine, pyrimidine, pyrrole, imidazoline, tetrahydrofuran,        tetrahydrothiophene, thiazole, thiophene, pyrrolidine,        dioxolane, pyrazoline, pyrazolidine, pyran, piperidine,        morpholine, thiomorpholine, or piperazine ring, in which the        proximal cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        ═O, —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c);        -   adamantyl unsubstituted or substituted with one, two, three,            or four substituents independently selected from the group            consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1d),            —NHR^(1d), —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₂,            —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH,            —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂; or        -   2,3-dihydrospiroindene-1,4′-piperidinyl unsubstituted or            substituted with one, two, three, or four substituents            independently selected from the group consisting of —Cl, —F,            —Br, —I, —NO₂, —OH, —NH₂, —R^(1d), —OR^(1d), —NHR^(1d),            —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₂,            —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH,            —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂;

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1b);

R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d);

R^(1c) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(1c) is unsubstituted or substituted with one, two, three,or four substituents independently selected from the group consisting of═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —NH₂, —OR^(1aa),—SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂, —C(O)R^(1aa), S(O)₂R^(1aa),S(O)₂NH₂, S(O)₂N(R^(1aa))₂, —C(O)NH₂, —C(O)N(H)(R^(1aa)),—C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h), —N(H)R^(1h)),—N(R^(1d))(R^(1h)) and —R^(1h);

R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1bb);

R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d),—SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d),—C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h);

R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(1e) is a monocyclic or bicyclic ring selected from the groupconsisting of cycloalkyl, heterocycle, aryl and heteroaryl, wherein eachring is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂,—NHR^(1aa), and —N(R^(1aa))₂;

R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, R^(1h); or R^(1g);

R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of R^(1h);

R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(1h) is unsubstituted or substituted with one or two orthree or four or five substituents independently selected from the groupconsisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂,—OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH,—C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂;

provided that when R¹ is proximal phenyl fused with a distal pyrrole,thiophene, furan, pyrazole, isoxazole, or isothiazole ring, the distalpyrrole, thiophene, furan, pyrazole, isoxazole, or isothiazole ring isnot substituted with —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, pyrrolidinyl, piperidyl, tetrahydropyridyl,pyrrolinyl, —C₁-alkyl substituted with pyrrolidinyl or piperidyl,—C₂-alkyl substituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d), —C₃-alkylsubstituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d), —C₄-alkyl substitutedwith —N(R^(1d))₂, —NH₂, or —NHR^(1d), —C₅-alkyl substituted with—N(R^(1d))₂, —NH₂, or —NHR^(1d), or —C₆-alkyl substituted with—N(R^(1d))₂, —NH₂, or —NHR^(1d);

and provided that when m is 0 and R² is phenyl, then R¹ is not proximalunfused phenyl;

A is N or CR⁶;

B is N or CR⁷;

E is N or CR⁸;

provided that only one of A, B and E is N;

R³ is —NH₂, —R^(3a), —OR^(3a), —NHR^(3a), —N(R^(3a))₂, —NHC(O)R^(3f),—N(R^(3d))C(O)R^(3f), —R^(3c), —OR^(3e), —SR^(3e), —NH(R^(3e)), or—N(R^(3d))(R^(3e));

R^(3a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(3b);

R^(3b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —NH₂,—CN, —OH, —OR^(3d), —R^(3c), —N(R^(3d))₂, and —NHR^(3d);

R^(3c) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(3c) is unsubstituted or substituted with one, two, three,or four substituents independently selected from the group consisting of—Cl, —F, —Br, —I, —OH, —R^(3aa), —NH₂, —OR^(3aa), —SR^(3aa), —NHR^(3aa),and —N(R^(3aa))₂;

R^(3d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(3aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(3bb);

R^(3bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(3d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(3d))₂, and —NHR^(3d);

R^(3e) is a monocyclic or bicyclic ring selected from the groupconsisting of cycloalkyl, heterocycle, aryl and heteroaryl, in whicheach ring is unsubstituted or substituted with one, two, three, or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —OH, —R^(3aa), —NH₂, —OR^(3aa), —SR^(3aa), —NHR^(3aa),and —N(R^(3aa))₂;

R^(3f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, or R^(3g);

R^(3g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of aryl and heteroaryl;

v is one, two, or three, and when v is two or three, R³ may be the sameor different;

R⁴ is —Cl, —F, —Br, —I, —NH₂, —R^(4a), —OR^(4a), —NR^(4a), —N(R^(4a))₂,—CN, —SR^(4a), or —SO₂R^(4a);

R^(4a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(4b);

R^(4b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(4c), —N(R^(4c))₂, —CN, —SR^(4c), and —SO₂R^(4c);

R^(4c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁵ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(5a), —OR^(5a), —NR^(5a),—N(R^(5a))₂, —CN, —SR^(5a), or —SO₂R^(5a);

R^(5a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(5b);

R^(5b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(5c), —N(R^(5c))₂, —CN, —SR^(5c), and —SO₂R^(5c);

R^(5c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁶ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(6a), —OR^(6a), —NHR^(6a),—N(R^(6a))₂, —CN, —SR^(6a), or —SO₂R^(6a);

R^(6a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(6b);

R^(6b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(6c), —N(R^(6c))₂, —CN, —SR^(6c), and —SO₂R^(6c);

R^(6c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁷ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(7a), —OR^(7a), —NHR^(7a),—N(R^(7a))₂, —CN, —SR^(7a), or —SO₂R^(7a);

R^(7a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(7b);

R^(7b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(7c), —N(R^(7c))₂, —CN, —SR^(7c), and —SO₂R^(7c);

R^(7c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁸ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(8a), —OR^(8a), —NHR^(8a),—N(R^(8a))₂, —CN, —SR^(8a), or —SO₂R^(8a);

R^(8a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(8b);

R^(8b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(8c), —N(R^(8c))₂, —CN, —SR^(8c), and —SO₂R^(8c);

R^(8c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; and

with the proviso that the following compounds are excluded:N-benzyl-1-(4-methoxyphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methylphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methoxyphenyl)-1H-tetrazol-5-amine; andN,1-bis(2,4-dimethylphenyl)-1H-tetrazol-5-amine.

In a second embodiment, the present invention provides a compound havingFormula (I) or Formula (II)

or a therapeutically acceptable salt, solvate, prodrug, or salt of aprodrug thereof, in which

R² is phenyl or pyridyl, wherein each R² is substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a),—N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(2b);

R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c);

R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

m is 0, 1, 2, or 3;

X and Y are independently selected from the group consisting of —H,—C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, and C₆-alkyl; or

X and Y together with the carbon atom to which they are attached form aring selected from the group consisting of cyclopropane, cyclobutane,cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, dioxolane, tetrahydropyran, piperidine, morpholine,thiomorpholine, and piperazine, each or which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a),—OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

Z is —H, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; or

Z and X together with the atoms to which they are attached form a ringselected from the group consisting of pyrrolidine, piperidine,morpholine, thiomorpholine, and piperazine;

R¹ is

-   -   proximal phenyl which is unfused or fused with a distal        cyclopentane, cyclohexane, cyclopentene, cyclohexene, dioxane,        dioxolane, naphthalene, benzene, furan, imidazole, isothiazole,        oxazole, isoxazole, pyrazine, pyrazole, pyridazine, pyridine,        pyrimidine, pyrrole, tetrahydrofuran, tetrahydrothiophene,        thiazole, thiophene, pyrrolidine, dioxolane, pyrazolidine,        pyran, piperidine, morpholine, thiomorpholine, oxazolidinone,        morpholinone, or piperazine ring, in which the proximal phenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a),        —N(R^(1a))₂—CN, —SR^(1a); —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)),        —SO₂N(R^(1a))₂, —C(O)R^(1d), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂,        —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂, —OR^(1c), —SR^(1e),        —SO₂R^(1e), —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)),        —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f),        —N(R^(1d))C(O)R^(1f) and —R^(1c);    -   proximal isoxazolyl, oxazolyl, pyrrolidinyl, pyridyl, thienyl,        pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, or        imidazopyridinyl, each of which is unfused or fused with a        distal cyclopentane, cyclohexane, cyclopentene, cyclohexene,        naphthalene, benzene, furan, imidazole, isothiazole, oxazole,        isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,        pyrrole, tetrahydrofuran, tetrahydrothiophene, thiazole,        thiophene, pyrrolidine, dioxolane, pyrazolidine, pyran,        piperidine, morpholine, thiomorpholine, or piperazine ring, in        which the proximal pyrrolidinyl, pyridyl, thienyl, pyrrolyl,        pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, pyrimidinyl, pyrazinyl, or imidazopyridinyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substitutents independently selected from the group consisting        of —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); or    -   proximal bicyclo[2.2.1]heptyl, cyclopentyl, cyclohexyl,        cyclopentenyl, or cyclohexenyl, each of which is unfused or        fused with a distal cyclopentane, cyclohexane, cyclopentene,        cyclohexene, naphthalene, benzene, furan, imidazole,        isothiazole, oxazole, isoxazole, pyrazine, pyrazole, pyridazine,        pyridine, pyrimidine, pyrrole, imidazoline, tetrahydrofuran,        tetrahydrothiophene, thiazole, thiophene, pyrrolidine,        dioxolane, pyrazoline, pyrazolidine, pyran, piperidine,        morpholine, thiomorpholine, or piperazine ring, in which the        proximal cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        ═O, —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c);        -   adamantyl unsubstituted or substituted with one, two, three,            or four substituents independently selected from the group            consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1d),            —OR^(1d), —NHR^(1d), —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d),            —SO₂NH₂, —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d),            —COOH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂; or        -   2,3-dihydrospiroindene-1,4′-piperidinyl unsubstituted or            substituted with one, two, three, or four substituents            independently selected from the group consisting of —Cl, —F,            —Br, —I, —NO₂, —OH, —NH₂, —R^(1d), —OR^(1d), —N(R^(1d))₂,            —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₂, —SO₂N(H)(R^(1d)),            —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH, —C(O)OR^(1d), —C(O)NH₂,            —C(O)N(H)(R^(1d)), and —C(O)N(R^(1d))₂;

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1b);

-   -   R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,        or —C₆-alkyl, each of which is substituted with one or two or        three substituents independently selected from the group        consisting of —F, —Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl,        —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c),        —N(R^(1d))₂, and —NHR^(1d);

R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl,imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl,tetrahydrofuryl, tetrahydrothienyl, thiazolyl, thienyl, pyrrolidinyl,dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl,3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, ═O, —NO₂, —CN,—OH, —R^(1aa), —NH₂, —OR^(1aa), —SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂,—C(O)R^(1aa), S(O)₂R^(1aa), S(O)₂NH₂, S(O)₂N(R^(1aa))₂, —C(O)NH₂,—C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h),—N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h);

R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1bb);

R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d),—SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d),—C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h);

R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl,azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein eachR^(1e) is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂,—NHR^(1aa), and —N(R^(1aa))₂;

R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, R^(1h); or R^(1g);

R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of R^(1h);

R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(1h) is unsubstituted or substituted with one or two orthree or four or five substituents independently selected from the groupconsisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂,—OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH,—C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂;

provided that when R¹ is proximal phenyl fused with a distal pyrrole,thiophene, furan, pyrazole, isoxazole, or isothiazole ring, the distalpyrrole, thiophene, furan, pyrazole, isoxazole, or isothiazole ring isnot substituted with —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, pyrrolidinyl, piperidyl, —C₁-alkyl substitutedwith pyrrolidinyl or piperidyl, —C₂-alkyl substituted with —N(R^(1d))₂,—NH₂, or —NHR^(1d), —C₃-alkyl substituted with —N(R^(1d))₂, —NH₂, or—NHR^(1d), —C₄-alkyl substituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d),—C₅-alkyl substituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d), or —C₆-alkylsubstituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d);

and provided that when m is 0 and R² is phenyl, then R¹ is not proximalunfused phenyl;

A is N or CR⁶;

B is N or CR⁷;

E is N or CR⁸;

provided that only one of A, B and E is N;

R³ is —NH₂, —R^(3a), —OR^(3a), —NHR^(3a), —N(R^(3a))₂, —NHC(O)R^(3f),—N(R^(3d))C(O)R^(3f), —^(3c), —OR^(3e), —SR^(3e), —NH(R^(3e)), or—N(R^(3d))(R^(3e));

R^(3a) is —C₁-alkyl, —C2-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(3b);

R^(3b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —NH₂,—CN, —OH, —OR^(3d), —R^(3c), —N(R^(3d))₂, and —NHR^(3d);

R^(3c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl,imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl,tetrahydrofuryl, tetrahydrothienyl thiazolyl, thienyl, pyrrolidinyl,dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl,3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, in which each ring is unsubstitutedor substituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, —OH, —R^(3aa),—NH₂, —OR^(3aa), —SR^(3aa), —NHR^(3aa), and —N(R^(3aa))₂;

R^(3d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(3aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(3bb);

R^(3bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(3d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(3d))₂, and —NHR^(3d);

R^(3e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl,azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein eachR^(3e) is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —OH, —R^(3aa), —OR^(3aa), —SR^(3aa), —NH₂, —NHR^(3aa),and —N(R^(3aa))₂;

R^(3f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, or R^(3g);

R^(3g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of aryl and heteroaryl;

v is one, two, or three, and when v is two or three, R³ may be the sameor different;

R⁴ is —Cl, —F, —Br, —I, —NH₂, —R^(4a), —OR^(4a), —NHR^(4a), —N(R^(4a))₂,—CN, —SR^(4a), or —SO₂R^(4a);

R^(4a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(4b);

R^(4b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(4c), —N(R^(4c))₂, —CN, —SR^(4c), and —SO₂R^(4c);

R^(4c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁵ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(5a), —OR^(5a), —NHR^(5a),—N(R^(5a))₂, —CN, —SR^(5a), —SO₂R^(5a);

R^(5a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(5b);

R^(5b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(5c), —N(R^(5c))₂, —CN, —SR^(5c), and —SO₂R^(5c);

R^(5c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁶ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(6a), —OR^(6a), —NHR^(6a),—N(R^(6a))₂, —CN, —SR^(6a), or —SO₂R^(6a);

R^(6a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(6b);

R^(6b) is —C₁-alkyl, —C₂-alkyl, —C3-alkyl, —C₄-alkyl, —C5-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(6c), —N(R^(6c))₂, —CN, —SR^(6c), and —SO₂R^(6c);

R^(6c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁷ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(7a), —OR^(7a), —NHR^(7a),—N(R^(7a))₂, —CN, —SR^(7a), or —SO₂R^(7a); R^(7a) is —C₁-alkyl,—C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or R^(7b);

R^(7b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(7e), —N(R^(7c))₂, —CN, —SR^(7c), and —SO₂R^(7c);

R^(7c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁸ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(8a), —OR^(8a), —NHR^(8a),—N(R^(8a))₂, —CN, —SR^(8a);

R^(8a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(8b);

R^(8b) is —C₁₋-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(8c), —N(R^(8c))₂, —CN, —SR^(8c), and —SO₂R^(8c);

R^(8c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; and

with the proviso that the following compounds are excluded:N-benzyl-1-(4-methoxyphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methylphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methoxyphenyl)-1H-tetrazol-5-amine; andN,1-bis(2,4-dimethylphenyl)-1H-tetrazol-5-amine.

In a third embodiment, the present invention relates to a compoundhaving Formula (I)

or a therapeutically acceptable salt, solvate, prodrug, or salt of aprodrug thereof, in which

R² is phenyl or pyridyl, in which each R² is substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a),—N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(2b);

R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c);

R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

m is 0, 1, 2, or 3;

X and Y are independently selected from the group consisting of —H,—C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, and C₆-alkyl; or

X and Y together with the carbon atom to which they are attached form aring selected from the group consisting of cyclopropane, cyclobutane,cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, dioxolane, tetrahydropyran, piperidine, morpholine,thiomorpholine, and piperazine, each of which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a),—OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a);

Z is —H, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; or

Z and X together with the atoms to which they are attached form a ringselected from the group consisting of pyrrolidine, piperidine,morpholine, thiomorpholine, and piperazine;

R¹ is

-   -   proximal phenyl which is unfused or fused with a distal        cyclopentane, cyclohexane, cyclopentene, cyclohexene, dioxane,        dioxolane, naphthalene, benzene, furan, imidazole, isothiazole,        oxazole, isoxazole, pyrazine, pyrazole, pyridazine, pyridine,        pyrimidine, pyrrole, tetrahydrofuran, tetrahydrothiophene,        thiazole, thiophene, pyrrolidine, dioxolane, pyrazolidine,        pyran, piperidine, morpholine, thiomorpholine, oxazolidinone,        morpholidinone, or piperazine ring, in which the proximal phenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a),        —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1d), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c);    -   proximal isoxazolyl, oxazolyl, pyrrolidinyl, pyridyl, thienyl,        pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, or        imidazopyridinyl, each of which is unfused or fused with a        distal cyclopentane, cyclohexane, cyclopentene, cyclohexene,        naphthalene, benzene, furan, imidazole, isothiazole, oxazole,        isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,        pyrrole, tetrahydrofuran, tetrahydrothiophene, thiazole,        thiophene, pyrrolidine, dioxolane, pyrazolidine, pyran,        piperidine, morpholine, thiomorpholine, or piperazine ring, in        which the proximal pyrrolidinyl, pyridyl, thienyl, pyrrolyl,        pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, pyrimidinyl, pyrazinyl, or imidazopyridinyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substitutents independently selected from the group consisting        of —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); or    -   proximal bicyclo[2.2.1]heptyl, cyclopentyl, cyclohexyl,        cyclopentenyl, or cyclohexenyl, each of which is unfused or        fused with a distal cyclopentane, cyclohexane, cyclopentene,        cyclohexene, naphthalene, benzene, furan, imidazole,        isothiazole, oxazole, isoxazole, pyrazine, pyrazole, pyridazine,        pyridine, pyrimidine, pyrrole, imidazoline, tetrahydrofuran,        tetrahydrothiophene, thiazole, thiophene, pyrrolidine,        dioxolane, pyrazoline, pyrazolidine, pyran, piperidine,        morpholine, thiomorpholine, or piperazine ring, in which the        proximal cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl        ring and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three, or four        substituents independently selected from the group consisting of        ═O, —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f) and —R^(1c);        -   adamantyl unsubstituted or substituted with one, two, three,            or four substituents independently selected from the group            consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1d),            —OR^(1d), —NHR^(1d), —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d),            —SO₂NH₂, —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d),            —COOH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂; or        -   2,3-dihydrospiroindene-1,4′-piperidinyl unsubstituted or            substituted with one, two, three, or four substituents            independently selected from the group consisting of —Cl, —F,            —Br, —I, —NO₂, —OH, —NH₂, —R^(1d), —OR^(1d), —NHR^(1d),            —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₂,            —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH,            —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂;

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1b);

R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d);

R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl,imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl,tetrahydrofuryl, tetrahydrothienyl, thiazolyl, thienyl, pyrrolidinyl,dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl,3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN,—OH, —R^(1aa), —NH₂, —OR^(1aa), —SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂,—C(O)R^(1aa), S(O)₂R^(1aa), S(O)₂NH₂, S(O)₂N(R^(1aa))₂, —C(O)NH₂,—C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h),—N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h);

R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1bb);

R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d),—SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d) —C(O)OH, —C(O)OR^(1d),—C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h);

R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl,azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein eachR^(1e) is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂,—NHR^(1aa), and —N(R^(1aa))₂;

R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, or R^(1g);

R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of aryl and heteroaryl;

provided that when R¹ is proximal phenyl fused with a distal pyrrole,thiophene, furan, pyrazole, isoxazole, or isothiazole ring, the distalpyrrole, thiophene, furan, pyrazole, isoxazole, or isothiazole ring isnot substituted with —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, pyrrolidinyl, piperidyl, —C₁-alkyl substitutedwith pyrrolidinyl or piperidyl, —C₂-alkyl substituted with —N(R^(1d))₂,—NH₂, or —NHR^(1d), —C₃-alkyl substituted with —N(R^(1d))₂, —NH₂, or—NHR^(1d), —C₄-alkyl substituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d),—C₅-alkyl substituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d), or —C₆-alkylsubstituted with —N(R^(1d))₂, —NH₂, or —NHR^(1d);

provided that when m is 0 and R² is phenyl, then R¹ is not proximalunfused phenyl; and with the proviso thatN-benzyl-1-(4-methoxyphenyl)-1H-tetrazol-5-amine is excluded.

For example, the third embodiment of the present invention provides acompound having Formula (I), or a therapeutically acceptable salt,prodrug, solvate, salt of a prodrug, or combination thereof, wherein R²is phenyl substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of —Cl, —F, —Br, —I,—NH₂, —R^(2a), —OR^(2a), —NR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and—SO₂R^(2a); R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, or R^(2b); R^(2b) is —C₁-alkyl, —C₂-alkyl,—C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which issubstituted with one, two or three substituents independently selectedfrom the group consisting of —Br, —I, —F, —Cl, —C₁-alkyl, —C₂-alkyl,—C₃-alkyl, —C₄-alkyl, —NH₂, —NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and—SO₂R^(2c); and R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, or —C₆-alkyl.

For example, the third embodiment of the present invention provides acompound having Formula (I), or a therapeutically acceptable salt,prodrug, solvate, salt of a prodrug, or combination thereof, wherein R²is phenyl substituted with one or two substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, —C₁-alkyl,—C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl.

For example, the third embodiment of the present invention provides acompound having Formula (I), or a therapeutically acceptable salt,prodrug, solvate, salt of a prodrug, or combination thereof, wherein R²is pyridyl substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of —Cl, —F, —Br, —I,—NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and—SO₂R^(2a); R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, or R^(2b); R^(2b) is —C₁-alkyl, —C₂-alkyl,—C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which issubstituted with one, two or three substituents independently selectedfrom the group consisting of —Br, —I, —F, —Cl, —C₁-alkyl, —C₂-alkyl,—C₃-alkyl, —C₄-alkyl, —NH₂, —NR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and—SO₂R^(2c); and R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, or —C₆-alkyl.

For example, the third embodiment of the present invention provides acompound having Formula (I), or a therapeutically acceptable salt,solvate, prodrug, or salt of a prodrug thereof, in which

R² is phenyl substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of —Cl,—F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN,—SR^(2a), and —SO₂R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(2b);

R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c);

R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl,

R¹ is

-   -   proximal unfused phenyl, unsubstituted or substituted with one,        two, three, or four substituents independently selected from the        group consisting of —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a),        —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a),        —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1d), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c);    -   proximal isoxazolyl, oxazolyl, pyrrolidinyl, pyridyl, thienyl,        pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, or        imidazopyridinyl, each of which is unfused or fused with a        distal cyclopentane, cyclohexane, cyclopentene, cyclohexene or        benzene ring, in which the proximal pyrrolidinyl, pyridyl,        thienyl, pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl,        thiazolyl, furyl, tetrahydrofuryl, pyrimidinyl, pyrazinyl, or        imidazopyridinyl rings and the distal ring are, independently of        each other, unsubstituted or substituted with one, two, three,        or four substitutents independently selected from the group        consisting of —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a),        —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a),        —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); or    -   proximal bicyclo[2.2.1]heptyl, cyclopentyl, cyclohexyl,        cyclopentenyl, or cyclohexenyl, each of which is fused with a        distal benzene, furan, imidazole, isothiazole, oxazole,        isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,        or pyrrole ring, in which the proximal cyclopentyl, cyclohexyl,        cyclopentenyl, or cyclohexenyl ring and the distal ring are,        independently of each other, unsubstituted or substituted with        one, two, three, or four substituents independently selected        from the group consisting of ═O, —Cl, —F, —Br, —I, —OH, NO₂,        —NH₂, —R^(1a), —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a),        —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂,        —C(O)R^(1a), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)),        —C(O)N(R^(1a))₂, —OR^(1e), —SR^(1e), —SO₂R^(1e),        —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)),        —N(R^(1d))(R^(1e)), —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and        —R^(1c);        -   adamantyl unsubstituted or substituted with one, two, three,            or four substituents independently selected from the group            consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1d),            —OR^(1d), —NHR^(1d), —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d),            —SO₂NH₂, —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d),            —COOH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂; or        -   2,3-dihydrospiroindene-1,4′-piperidinyl unsubstituted or            substituted with one, two, three, or four substituents            independently selected from the group consisting of —Cl, —F,            —Br, —I, —NO₂, —OH, —NH₂, —R^(1d), —OR^(1d), —NHR^(1d),            —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₁₂,            —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH,            —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂;

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1b);

R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d);

R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl,imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl,tetrahydrofuryl, tetrahydrothienyl, thiazolyl, thienyl, pyrrolidinyl,dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl,3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, ═O, —OH,—R^(1aa), —SR^(1aa), —NH₂, —NO₂, —CN, —OR^(1aa), —NHR^(1aa),—N(R^(1aa))₂; —C(O)R^(1aa), S(O)₂R^(1aa), S(O)₂NH₂, S(O)₂N(R^(1aa))₂,—C(O)NH₂, —C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa),—OR^(1h), —N(H)R^(1h)), —N(R^(1d))(R^(1h)) and R^(1h);

R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1bb);

R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d),—SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d) —C(O)OH, —C(O)OR^(1d),—C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h);

R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl,azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein eachR^(1e) is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂,—NHR^(1aa), and —N(R^(1aa))₂;

R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, R^(1h); or R^(1g); and

R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of R^(1h);

For example, the third embodiment of the present invention provides acompound having Formula (I), or a therapeutically acceptable salt,solvate, prodrug, or salt of a prodrug thereof, in which

R² is phenyl substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of —Cl,—F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN,—SR^(2a), and —SO₂R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(2b);

R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c);

R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl,

R¹ is

-   -   proximal unfused phenyl, unsubstituted or substituted with one,        two, three, or four substituents independently selected from the        group consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1a),        —OR^(1a), —NR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a),        —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1d), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c);    -   proximal isoxazolyl, oxazolyl, pyrrolidinyl, pyridyl, thienyl,        pyrrolyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, furyl,        tetrahydrofuryl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, or        imidazopyridinyl ring, each of which is unfused and each of        which is, independently of each other, unsubstituted or        substituted with one, two, three, or four substitutents        independently selected from the group consisting of —Cl, —F,        —Br, —I, —NO₂, —OH, —NH₂, —R^(1a)OR^(1a), —NHR^(1a),        —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f),        —N(R^(1d))C(O)R^(1f), and —R^(1c); or    -   proximal bicyclo[2.2.1]heptyl, cyclopentyl, cyclohexyl,        cyclopentenyl, or cyclohexenyl ring, each of which is unfused        and each of which is, independently of each other, unsubstituted        or substituted with one, two, three, or four substituents        independently selected from the group consisting of —Cl, —F,        —Br, —I, ═O, —NO₂, —OH, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a),        —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f),        —N(R^(1d))C(O)R^(1f), and —R^(1c);        -   adamantyl unsubstituted or substituted with one, two, three,            or four substituents independently selected from the group            consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1d),            —OR^(1d), —NHR^(1d), —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d),            —SO₂NH₂, —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d),            —COOH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂; or        -   2,3-dihydrospiroindene-1,4′-piperidinyl unsubstituted or            substituted with one, two, three, or four substituents            independently selected from the group consisting of —Cl, —F,            —Br, —I, —NO₂, —OH, —NH₂, —R^(1d), —OR^(1d), —NHR^(1d),            —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₂,            —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH,            —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂;

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1b);

R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and NHR^(1d);

R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl,imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl,tetrahydrofuryl, tetrahydrothienyl, thiazolyl, thienyl, pyrrolidinyl,dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl,3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN,—OH, —R^(1aa), —SR^(1aa), —NH₂, —OR^(1aa), —NHR^(1aa), —N(R^(1aa))₂—C(O)R^(1aa), S(O)₂R^(1aa), S(O)₂NH₂, S(O)₂N(R^(1aa))₂, —C(O)NH₂,—C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h),—N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h);

R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1bb);

R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —NO₂, —CN, haloalkyl, haloalkoxy, —OR^(1d),—SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d),—C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h);

R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl,azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein eachR^(1e) is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —OH, —NO₂, —CN, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂,—NHR^(1aa), and —N(R^(1aa))₂;

R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, R^(1h) or R^(1g); and

R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of R^(1h)

For example, the present invention provides a compound having Formula(I), or a therapeutically acceptable salt, solvate, prodrug, or salt ofa prodrug thereof, in which

R² is phenyl substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of —Cl,—F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN,—SR^(2a), and —SO₂R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(2b);

R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c) and —SO₂R^(2c);

R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R¹ is

-   -   proximal unfused phenyl, unsubstituted or substituted with one,        substituent selected from the group consisting of —Cl, —F, —Br,        —I, —NO₂, —OH, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a), —N(R^(1a))₂,        —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)),        —SO₂N(R^(1a))₂, —C(O)R^(1d), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂,        —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂, —OR^(1e), —SR^(1e),        —SO₂R^(1e), —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)),        —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f),        —N(R^(1d))C(O)R^(1f), and —R^(1c);    -   proximal isoxazolyl, oxazolyl, pyridyl, thienyl, pyrrolyl,        tetrahydropyranyl, or pyrazolyl, each of which is unfused or        fused with a distal cyclopentane, cyclohexane, or benzene ring,        in which the proximal pyridyl, thienyl, pyrrolyl, or pyrazolyl        rings and the distal ring are, independently of each other,        unsubstituted or substituted with one, two, three or four        substitutents independently selected from the group consisting        of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1a), —OR^(1a),        —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂,        —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH,        —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂,        —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)),        —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)),        —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); or    -   proximal cyclopentyl or cyclohexyl, each of which is fused with        a distal benzene or pyridine ring, in which the proximal        cyclopentyl or cyclohexyl ring and the distal ring are,        independently of each other, unsubstituted or substituted with        one, two, three or four substituents independently selected from        the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂—OH, —NH₂,        —R^(1a), —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a),        —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂,        —C(O)R^(1a), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)),        —C(O)N(R^(1a))₂, OR^(1e), —SR^(1e), —SO₂R^(1e),        —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)),        —N(R^(1d))(R^(1e)), —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and        —R^(1c);        -   adamantyl unsubstituted or substituted with one, two, three,            or four substituents independently selected from the group            consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1d),            —OR^(1d), —NHR^(1d), —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d),            —SO₂NH₂, —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d),            —COOH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂; or        -   2,3-dihydrospiroindene-1,4′-piperidinyl unsubstituted or            substituted with one, two, three, or four substituents            independently selected from the group consisting of —Cl, —F,            —Br, —I, —NO₂, —OH, —NH₂, —R^(1d), —OR^(1d), —NHR^(1d),            —N(R^(1d))₂, —CN, —SR^(1d), —SO₂R^(1d), —SO₂NH₂,            —SO₂N(H)(R^(1d)), —SO₂N(R^(1d))₂, —C(O)R^(1d), —COOH,            —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), and            —C(O)N(R^(1d))₂;

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1b);

R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d);

R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl,imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl,tetrahydrofuryl, tetrahydrothienyl, thiazolyl, thienyl, pyrrolidinyl,dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl,3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN,—OH, —R^(1aa), —NH₂, —OR^(1aa), —SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂,—C(O)R^(1aa), S(O)₂R^(1aa), S(O)₂NH₂, S(O)₂N(R^(1aa))₂, —C(O)NH₂,—C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h),—N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h);

R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(1bb);

R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d),—SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d),—C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h);

R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl or—C₆-alkyl;

R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl,azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein eachR^(1e) is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂,—NHR^(1aa), and —N(R^(1aa))₂;

R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, or R^(1h); R^(1g); and

R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of R^(1g);

R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, inwhich each R^(1h) is unsubstituted or substituted with one or two orthree or four or five substituents independently selected from the groupconsisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂,—OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH,—C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂,—S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂.

For example, the third embodiment of the present invention provides acompound having Formula (I), or a therapeutically acceptable salt,solvate, prodrug, salt of a prodrug thereof, in which

R² is phenyl substituted with two substituents independently selectedfrom the group consisting of —Cl, —F, —Br, —I and R^(2a);

R^(2a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

m is 0, 1 or 2;

X and Y are independently selected from the group consisting of —H,—C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, and C₆-alkyl;

Z is —H, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R¹ is

-   -   proximal unfused phenyl, unsubstituted or substituted with one,        substituent selected from the group consisting of —R^(1a),        —N(R^(1a))₂, —SR^(1a), —O(pyridyl), —O(phenyl), —O(pyrazinyl),        pyrrolyl or morpholinyl; in which the phenyl moiety of        —O(phenyl) is unsubstituted or substituted with one substituent        independently selected from the group consisting of —Cl, —F,        —Br, and —I;    -   proximal unfused pyridyl, unsubstituted or substituted with one        —R^(1a) substituent;    -   proximal pyridyl fused with a distal cyclopentane, cyclohexane,        or benzene ring, in which the proximal pyridyl and the distal        ring are, independently of each other, unsubstituted or        substituted with one —R^(1a) substituent;    -   proximal thienyl, pyrrolyl, or pyrazolyl, each of which is        unfused and each of which is independently unsubstituted or        substituted with one or two substitutents independently selected        from the group consisting of —R^(1a), unsubstituted phenyl and        phenyl substituted with one —R^(1a) substituent; or    -   proximal cyclopentyl or cyclohexyl, each of which is fused with        a distal benzene or pyridine ring, in which the proximal        cyclopentyl or cyclohexyl ring and the distal ring are,        independently of each other, unsubstituted or substituted with        one —R^(1a) substituent; and    -   R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl        or —C₆-alkyl.

For example, the third embodiment of the present invention relates to acompound having Formula (I), or a therapeutically acceptable salt,solvate, prodrug or salt of a prodrug thereof, in which

R² is phenyl substituted with two substituents independently selectedfrom the group consisting of —Cl and —C₁-alkyl;

m is 0, 1 or 2;

X and Y are independently selected from the group consisting of —H and—C₁-alkyl;

Z is H or —C₁-alkyl; and

R¹ is

-   -   proximal unfused phenyl, unsubstituted or substituted with one,        substituent selected from the group consisting of —C₁-alkyl,        —N(C₁-alkyl)₂, —S(C₁-alkyl), —O(pyridyl), —O(phenyl),        —O(pyrazinyl), pyrrolyl or morpholinyl; in which the phenyl        moiety of —O(phenyl) is unsubstituted or substituted with one —F        substituent;    -   proximal unfused pyridyl, unsubstituted or substituted with one        —C₁-alkyl substituent;    -   proximal pyridyl fused with a distal cyclopentane, cyclohexane,        or benzene ring, in which the proximal pyridyl ring and the        distal ring are, independently of each other, unsubstituted or        substituted with one —C₁-alkyl substituent;    -   proximal thienyl, pyrrolyl, or pyrazolyl, each of which is        unfused and each of which is independently unsubstituted or        substituted with one or two substitutents independently selected        from the group consisting of —C₁-alkyl, unsubstituted phenyl and        phenyl substituted with one —C₁-alkyl; or    -   proximal cyclopentyl or cyclohexyl, each of which is fused with        a distal benzene or pyridine ring, in which the proximal        cyclopentyl or cyclohexyl ring and the distal ring are,        independently of each other, unsubstituted or substituted with        one —C₁-alkyl substituent.

For example, the third embodiment of the present invention relates to acompound having Formula (I), or a therapeutically acceptable salt,solvate, prodrug or salt of a prodrug thereof, in which,

R² is phenyl substituted with two substituents independently selectedfrom the group consisting of —Cl and —C₁-alkyl;

-   -   m is 0;    -   Z and X together with the atoms to which they are attached form        a ring selected from the group consisting of pyrrolidine,        piperidine, morpholine, thiomorpholine, and piperazine;    -   Y is independently selected from the group consisting of —H,        —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, and        C₆-alkyl;

R¹ is

-   -   proximal unfused phenyl, unsubstituted or substituted with one,        substituent selected from the group consisting of —R^(1a),        —N(R^(1a))₂, —SR^(1a), —O(pyridyl), —O(phenyl), —O(pyrazinyl),        pyrrolyl or morpholinyl; in which the phenyl moiety of        —O(phenyl) is unsubstituted or substituted with one substituent        independently selected from the group consisting of —Cl, —F,        —Br, and —I;    -   proximal unfused pyridyl, unsubstituted or substituted with one        —R^(1a) substituent;    -   proximal pyridyl fused with a distal cyclopentane, cyclohexane,        or benzene ring, in which the proximal pyridyl and the distal        ring are, independently of each other, unsubstituted or        substituted with one —R^(1a) substituent;    -   proximal thienyl, pyrrolyl, or pyrazolyl, each of which is        unfused and each of which is independently unsubstituted or        substituted with one or two substitutents independently selected        from the group consisting of —R^(1a), unsubstituted phenyl and        phenyl substituted with one —R^(1a) substituent; or    -   proximal cyclopentyl or cyclohexyl, each of which is fused with        a distal benzene or pyridine ring, in which the proximal        cyclopentyl or cyclohexyl ring and the distal ring are,        independently of each other, unsubstituted or substituted with        one —R^(1a) substituent; and

R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl or—C₆-alkyl.

For example, the third embodiment of the present invention provides acompound having Formula (I), or a therapeutically acceptable salt,solvate, prodrug or salt of a prodrug thereof, in which

R² is 2,3-dichlorophenyl or 2-methylphenyl;

m is 0, 1 or 2;

X and Y are independently selected from the group consisting of —H andmethyl;

Z is —H or methyl; and

R¹ is 2-methylphenyl, 2-(morpholin-4-yl)phenyl, 2-(dimethylamino)phenyl,2-(pyridine-2-yloxy)phenyl, phenyl, 3-(dimethylamino)phenyl,2-(methylthio)phenyl, 2-(4-fluorophenoxy)phenyl,3-(pyrazin-2-yloxy)phenyl, 2-(1H-pyrrol-1-yl)phenyl,4-(pyridine-2-yloxy)phenyl, 3-(pyridine-2-yloxy)phenyl,4-(morpholin-4-yl)phenyl, pyridine-4-yl, pyridine-3-yl, pyridine-2-yl,quinolin-4-yl, 3-methylpyridin-4-yl,6,7-dihydro-5H-cyclopenta[b]pyridine-3-yl,5,6,7,8-tetrahydroquinolin-3-yl, 1-methyl-1H-pyrrol-2-yl,2-methylthien-3-yl, 3-methyl-1-phenyl-1H-pyrazol-5-yl,1,5-dimethyl-1H-pyrazol-4-yl, 2,3-dihydro-1H-inden-1-yl, or5,6,7,8-tetrahydroquinolin-5-yl.

In a fourth embodiment, the present invention provides a compound havingFormula (II),

or a therapeutically acceptable salt, solvate, prodrug, or salt of aprodrug thereof, in which

Z is —H, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

A is N or CR⁶;

B is N or CR⁷;

E is N or CR⁸;

provided that only one of A, B and E is N;

R³ is —NH₂, —R^(3a), —OR^(3a), —NHR^(3a), —N(R^(3a))₂, —NHC(O)R^(3f),—N(R^(3d))C(O)R^(3f), —R^(3c), —OR^(3e), —SR^(3e), —NH(R^(3e)), or—N(R^(3d))(R^(3e));

R^(3a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(3b);

R^(3b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —NH₂,—CN, —OH, —OR^(3d), —R^(3c), —N(R^(3d))₂, and —NHR^(3d);

R^(3c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl,imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl,tetrahydrofuryl, tetrahydrothienyl thiazolyl, thienyl, pyrrolidinyl,dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl,3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted orsubstituted with one, two, three, or four substituents independentlyselected from the group consisting of —Cl, —F, —Br, —I, —OH, —R^(3aa),—NH₂, —OR^(3aa), —SR^(3aa), —NHR^(3aa) and —N(R^(3aa))₂;

R^(3d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(3aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or —R^(3bb);

R^(3bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —F,—Cl, —Br, —I, —NH₂, —OH, —OR^(3d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl,—C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(3d))₂, and —NHR^(3d);

R^(3e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl,azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein eachR^(3e) is unsubstituted or substituted with one, two, three or foursubstituents independently selected from the group consisting of ═O,—Cl, —F, —Br, —I, —OH, —R^(3aa), —OR^(3aa), —NH₂, —NHR^(3aa), and—N(R^(3aa))₂;

R^(3f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, or R^(3g);

R^(3g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of aryl and heteroaryl;

v is one, two, or three, and when v is two or three, R³ may be the sameor different;

R⁴ is —Cl, —F, —Br, —I, —NH₂, —R^(4a), —OR^(4a), —NHR^(4a), —N(R^(4a))₂,—CN, —SR^(4a), or —SO₂R^(4a);

R^(4a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(4b);

R^(4b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(4c), —N(R^(4c))₂, —CN, —SR^(4c), and —SO₂R^(4c);

R^(4c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁵ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(5a), —OR^(5a), —NHR^(5a),—N(R^(5a))₂, —CN, —SR^(5a), or —SO₂R^(5a);

R^(5a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(5b);

R^(5b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(5c), —N(R^(5c))₂, —CN, —SR^(5c), and —SO₂R^(5c);

R^(5c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁶ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(6a), —OR^(6a), —NHR^(6a),—N(R^(6a))₂, —CN, —SR^(6a), or —SO₂R^(6a);

R^(6a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(6b);

R^(6b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(6c), —N(R^(6c))₂, —CN, —SR^(6c), and —SO₂R^(6c);

R^(6c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁷ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(7a), —OR^(7a), —NHR^(7a),—N(R^(7a))₂, —CN, —SR^(7a), or —SO₂R^(7a);

R^(7a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(7b);

R^(7b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(7c), —N(R^(7c))₂, —CN, —SR^(7c), and —SO₂R^(7c);

R^(7c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁸ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(8a), —OR^(8a), —NHR^(8a),—N(R^(8a))₂, —CN, —SR^(8a), or —SO₂R^(8a);

R^(8a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C5-alkyl,—C₆-alkyl, or R^(8b);

R^(8b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(8c), —N(R^(8c))₂, —CN, —SR^(8c), and —SO₂R^(8c);

R^(8c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; and with the proviso that the following compounds areexcluded: N,1-bis(4-methylphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methoxyphenyl)-1H-tetrazol-5-amine; andN,1-bis(2,4-dimethylphenyl)-1H-tetrazol-5-amine.

For example, the present invention provides a compound having Formula(II), or a therapeutically acceptable salt, solvate, prodrug, or salt ofa prodrug thereof, in which

A is CR⁶;

B is CR⁷;

E is CR⁸;

R⁴ is —Cl, —F, —Br, —I, —NH₂, —R^(4a), —OR^(4a), —NHR^(4a), —N(R^(4a))₂,—CN, —SR^(4a), or —SO₂R^(4a);

R^(4a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(4b);

R^(4b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(4c), —N(R^(4c))₂, —CN, —SR^(4c), and —SO₂R^(4c);

R^(4c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁵ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(5a), —OR^(5a), —NHR^(5a),—N(R^(5a))₂, —CN, —SR^(5a), or —SO₂R^(5a);

R^(5a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(5b);

R^(5b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(5c), —N(R^(5c))₂, —CN, —SR^(5c), and —SO₂R^(5c);

R^(5c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁶ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(6a), —OR^(6a), —NHR^(6a),—N(R^(6a))₂, —CN, —SR^(6a), —SO₂ ^(6a);

R^(6a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(6b);

R^(6b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(6c), —N(R^(6c))₂, —CN, —SR^(6c), and —SO₂R^(6c);

R^(6c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁷ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(7a), —OR^(7a), —NHR^(7a),—N(R^(7a))₂, —CN, —SR^(7a), or —SO₂R^(7a);

R^(7a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(7b);

R^(7b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(7c), —N(R^(7c))₂, —CN, —SR^(7c), and —SO₂R^(7c);

R^(7c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁸ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(8a), —OR^(8a), —NHR^(8a),—N(R^(8a))₂, —CN, —SR^(8a), or —SO₂R^(8a);

R^(8a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(8b);

R^(8b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(8c), —N(R^(8c))₂, —CN, —SR^(8c), and —SO₂R^(8c); and

R^(8c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl; with the proviso that the following compounds are excluded:N,1-bis(4-methylphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methoxyphenyl)-1H-tetrazol-5-amine; andN,1-bis(2,4-dimethylphenyl)-1H-tetrazol-5-amine.

For example, the fourth embodiment of the present invention provides acompound having Formula (II), or a therapeutically acceptable salt,solvate, prodrug or salt of a prodrug thereof, in which

A is CR⁶;

B is CR⁷;

E is CR⁸;

R⁴ is —Cl, —F, —Br, —I, —NH₂, —R^(4a), —OR^(4a), —NHR^(4a), —N(R^(4a))₂,—CN, —SR^(4a), or —SO₂R^(4a);

R^(4a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(4b);

R^(4b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(4c), —N(R^(4c))₂, —CN, —SR^(4c), and —SO₂R^(4c);

R^(4c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁵ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(5a), —OR^(5a), —NHR^(5a),—N(R^(5a))₂, —CN, —SR^(5a), or —SO₂R^(5a);

R^(5a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(5b);

R^(5b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(5c), —N(R^(5c))₂, —CN, —SR^(5c), and —SO₂R^(5c);

R^(5c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁶ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(6a), —OR^(6a), —NHR^(6a),—N(R^(6a))₂, —CN, —SR^(6a), or —SO₂R^(6a);

R^(6a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(6b);

R^(6b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(6c), —N(R^(6c))₂, —CN, —SR^(6c), and —SO₂R^(6c);

R^(6c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁷ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(7a), —OR^(7a), —NHR^(7a),—N(R^(7a))₂, —CN, —SR^(7a), or —SO₂R^(7a);

R^(7a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(7c),

R^(7b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(7c), —N(R^(7c))₂, —CN, —SR^(7c), and —SO₂R^(7c);

R^(7c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R⁸ is —H, —Cl, —F, —Br, —I, —NH₂, —R^(8a), —OR^(8a), —NHR^(8a),—N(R^(8a))₂, —CN, —SR^(8a), or SO₂R^(8a);

R^(8a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, or R^(8b);

R^(8b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting of —Br,—I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂,—NHR^(8c), —N(R^(8c))₂, —CN, —SR^(8c), and —SO₂R^(8c);

R^(8c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R³ is —NH₂, —R^(3a), —OR^(3a), —NH(R^(3a)), —N(R^(3a))₂, —NHC(O)R^(3f),or —N(R^(3d))C(O)R^(3f);

R^(3a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl or R^(3b);

R^(3b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one or two or threesubstituents independently selected from the group consisting —NH₂, —CN,—OH, —OR^(3d), —N(R^(3d))₂, and —NR^(3d);

R^(3d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R^(3f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl,—C₆-alkyl, aryl, heteroaryl, or R^(3g);

R^(3g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl, each of which is substituted with one substituent selectedfrom the group consisting of aryl and heteroaryl;

v is one, two, or three, and when v is two or three, R³ may be the sameor different; with the proviso that the following compounds areexcluded: N,1-bis(4-methylphenyl)-1H-tetrazol-5-amine;N,1-bis(4-methoxyphenyl)-1H-tetrazol-5-amine; andN,1-bis(2,4-dimethylphenyl)-1H-tetrazol-5-amine.

For example, the fourth embodiment of the present invention provides acompound having Formula (II), or a therapeutically acceptable salt,solvate, prodrug, or salt of a prodrug thereof, in which

A is CR⁶;

B is CR⁷;

E is CR⁸;

R⁴ is —Cl, —F, —Br, —I, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl, or —C₆-alkyl;

R⁵ is —H, —Cl, —F, —Br, —I, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl,—C₅-alkyl or —C₆-alkyl;

R⁶ is —H;

R⁷ is —H;

R⁸ is —H;

Z is —H, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or—C₆-alkyl;

R³ is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl or—C₆-alkyl; and

v is one; with the proviso that the following compounds are excluded:N,1-bis(4-methylphenyl)-1H-tetrazol-5-amine; andN,1-bis(2,4-dimethylphenyl)-1H-tetrazol-5-amine.

For example, the fourth embodiment of the present invention provides acompound having Formula (II), or a therapeutically acceptable salt,ester, solvate, or prodrug thereof, in which A is CR⁶; B is CR⁷; E isCR⁸; R⁴ is —Cl, R⁵ is —Cl, R⁶ is —H; R⁷ is —H; R⁸ is —H; Z is —H; R³ is—C₁-alkyl; and v is one.

A representative example of a compound having Formula (II) includes, butis not limited to,1-(2,3-dichlorophenyl)-N-(2-methylphenyl)-1H-tetrazol-5-amine, or atherapeutically acceptable salt, solvate, prodrug, salt of a prodrug, orcombination thereof.

In a fifth embodiment the present invention a relates to a method fortreating a P2X₇ mediated disease in a patient in need of such treatment,which comprises administering to said patient a therapeuticallyeffective amount of a compound of Formula (I) or Formula (II), or atherapeutically acceptable salt, solvate, prodrug, salt of a prodrug, orcombination thereof.

For example, the present invention relates to a method for treating acondition selected from the group consisting of arthritis (includingpsoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout,traumatic arthritis, rubella arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and acute synovitis), inflammatory boweldisease, Crohn's disease, emphysema, acute respiratory distresssyndrome, adult respiratory distress syndrome, asthma, bronchitischronic sarcoidosis, allergic reactions, allergic contacthypersensitivity, eczema, contact dermatitis, psoriasis, sunburn,cancer, tissue ulceration, restenosis, periodontal disease,epidermolysis bullosa, osteoporosis, bone resorption disease,atherosclerosis, aortic aneurysm, congestive heart failure,neurodegeneration, inflammation, Alzheimer's disease, Parkinson'sdisease, peripheral neuropathy, depression, spinal cord injury, pain,burns, autoimmune disorders, and to promote neuroregeneration in apatient in need of such treatment, which comprises administering to saidpatient a therapeutically effective amount of a compound of Formula (I)or Formula (II), or a therapeutically acceptable salt, solvate, prodrug,salt of a prodrug, or combination thereof.

For example, the present invention provides a method for treatingdepression, spinal cord injury, neurodegeneration, chronic inflammatorypain or neuropathic pain in a patient, which comprises administering toa patient in need of such treatment a therapeutically effective amountof a compound having Formula (I) or Formula (II), or a therapeuticallyacceptable salt, solvate, prodrug, salt of a prodrug, or combinationthereof.

For example, the present invention provides a method for treatinginflammation in a patient, which comprises administering to a patient inneed of such treatment a therapeutically effective amount of a compoundhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof.

For example, the present invention provides a method for treatingneurodegeneration in a patient, which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa compound having Formula (I) or Formula (II), or a therapeuticallyacceptable salt, solvate, prodrug, salt of a prodrug, or combinationthereof.

For example, the present invention provides a method for treatingCrohn's disease in a patient, which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound having Formula (I) or Formula (II), or a therapeuticallyacceptable salt, solvate, prodrug, salt of a prodrug, or combinationthereof.

In a sixth embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof, and apharmaceutically acceptable carrier.

The present invention relates to a pharmaceutical composition for thetreatment of P2X₇ mediated disease in a patient, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound having Formula (I) or Formula (II), or atherapeutically acceptable salt, solvate, prodrug, salt of a prodrug, orcombination thereof, and a pharmaceutically acceptable carrier.

For example, the present invention relates to a pharmaceuticalcomposition for the treatment of a condition selected from the groupconsisting of arthritis (including psoriatic arthritis, Reiter'ssyndrome, rheumatoid arthritis, gout, traumatic arthritis, rubellaarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andacute synovitis), inflammatory bowel disease, Crohn's disease,emphysema, acute respiratory distress syndrome, adult respiratorydistress syndrome, asthma, bronchitis chronic sarcoidosis, allergicreactions, allergic contact hypersensitivity, eczema, contactdermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis,periodontal disease, epidermolysis bullosa, osteoporosis, boneresorption disease, atherosclerosis, aortic aneurysm, congestive heartfailure, neurodegeneration, inflammation, Alzheimer's disease,Parkinson's disease, peripheral neuropathy, spinal cord injury,depression, pain, burns, autoimmune disorders, and to improveneuroregeneration in a patient, comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof, and apharmaceutically acceptable carrier.

For example, the present invention provides a method for treatingchronic inflammatory pain or neuropathic pain in a patient, comprisingadministering to the patient in need of such treatment a therapeuticallyeffective amount of a compound having Formula (I) or Formula (II), or atherapeutically acceptable salt, solvate, prodrug, salt of a prodrug, orcombination thereof, and a pharmaceutically acceptable carrier.

For example, the present invention provides a method for treatingCrohn's disease in a patient, comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof, and apharmaceutically acceptable carrier.

For example, the present invention provides a method for treatingneurodegeneration in a patient, comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof, and apharmaceutically acceptable carrier.

For example, the present invention provides a method for treatingdepression in a patient, comprising administering to a patient in needof such treatment a therapeutically effective amount of a compoundhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof, and apharmaceutically acceptable carrier.

For example, the present invention provides a method for treating spinalcord injury in a patient, comprising administering to a patient in needof such treatment a therapeutically effective amount of a compoundhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof, and apharmaceutically acceptable carrier.

In a seventh embodiment, the present invention provides the use of acompound having Formula (I) or Formula (II), or a therapeuticallyacceptable salt, solvate, prodrug, salt of a prodrug, or combinationthereof, to prepare a medicament for the treatment of a P2X₇ mediateddisease in a patient.

For example, the present invention provides the use of a compound ofhaving Formula (I) or Formula (II), or a therapeutically acceptablesalt, solvate, prodrug, salt of a prodrug, or combination thereof, toprepare a medicament for the treatment of chronic inflammatory pain orneuropathic pain in a patient.

For example, the present invention provides the use of a compound havingFormula (I) or Formula (II), or a therapeutically acceptable salt,solvate, prodrug, salt of a prodrug, or combination thereof, to preparea medicament for the treatment of a condition selected from the groupconsisting of arthritis (including psoriatic arthritis, Reiter'ssyndrome, rheumatoid arthritis, gout, traumatic arthritis, rubellaarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andacute synovitis), inflammatory bowel disease, Crohn's disease,emphysema, acute respiratory distress syndrome, adult respiratorydistress syndrome, asthma, bronchitis chronic sarcoidosis, allergicreactions, allergic contact hypersensitivity, eczema, contactdermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis,periodontal disease, epidermolysis bullosa, osteoporosis, boneresorption disease, atherosclerosis, aortic aneurysm, congestive heartfailure, neurodegeneration, inflammation, depression, neurodegeneration,spinal cord injury, Alzheimer's disease, Parkinson's disease, peripheralneuropathy, pain, burns, and autoimmune disorders in a patient.

In an eighth embodiment, the present invention provides a method forinhibiting P2X₇ activity in a patient, comprising administering to thepatient a therapeutically effective amount of a compound of havingFormula (I) or Formula (II), or a therapeutically acceptable salt,solvate, prodrug, salt of a prodrug, or combination thereof.

Compounds of the invention were named by ACD/ChemSketch version 5.06(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names consistent with ACD nomenclature.

When any variable (for example R^(1a), R^(1b), R^(1c), R^(1d), R^(1e),R^(1f), R^(1g), R^(1aa), R^(1bb), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b), R^(3c), R^(3d), R^(3e), R^(3f), R^(3g), R^(3aa), R^(3bb),R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) R^(5c), R^(6a), R^(6b), R^(6c),R^(7a), R^(7b), R^(7c), R^(8a), R^(8b), R^(8c), etc.) occurs more thanone time in any substituent or in the compound of Formula (I) or (II) orany other formula herein, its definition on each occurrence isindependent of its definition at every other occurrence. In addition,combinations of substituents are permissible only if such combinationsresult in stable compounds. Stable compounds are compounds which can beisolated in a useful degree of purity from a reaction mixture.

As used throughout this specification and the appended claims, thefollowing terms have the following meanings.

The term “C₁-alkyl” means methyl.

The term “C₂-alkyl” means ethyl.

The term “C₃-alkyl” means prop-1-yl and prop-2-yl(isopropyl).

The term “C₄-alkyl” means but-1-yl, but-2-yl, 2-methylprop-1-yl, and2-methylprop-2-yl(tert-butyl).

The term “C₅-alkyl” means 2,2-dimethylprop-1-yl(neo-pentyl),2-methylbut-1-yl, 2-methylbut-2-yl, 3-methylbut-1-yl, 3-methylbut-2-yl,pent-1-yl, pent-2-yl, and pent-3-yl.

The term “C₆-alkyl” means 2,2-dimethylbut-1-yl, 2,3-dimethylbut-1-yl,2,3-dimethylbut-2-yl, 3,3-dimethylbut-1-yl, 3,3-dimethylbut-2-yl,2-ethylbut-1-yl, hex-1-yl, hex-2-yl, hex-3-yl, 2-methylpent-1-yl,2-methylpent-2-yl, 2-methylpent-3-yl, 3-methylpent-1-yl,3-methylpent-2-yl, 3-methylpent-3-yl, 4-methylpent-1-yl, and4-methylpent-2-yl.

The term “aryl” as used herein, refers to a phenyl group, or a bicyclichydrocarbon fused ring systems wherein one or more of the rings is aphenyl group. Bicyclic fused ring systems have a phenyl group fused to amonocyclic cycloalkenyl group, as defined herein, a monocycliccycloalkyl group, as defined herein, or another phenyl group.Representative examples of aryl groups include, but not limited to,indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl. The arylgroups of the present invention can be substituted or unsubstituted, andare connected to the parent molecular moiety through any substitutablecarbon atom of the group.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic,partially unsaturated, monocyclic hydrocarbon ring system, having threeto ten carbon atoms and zero heteroatom. Representative examples ofcycloalkenyl groups include, but not limited to, adamantyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl.The cycloalkenyl groups of the present invention can be unsubstituted orsubstituted, and are attached to the parent molecular moiety through anysubstitutable carbon atom of the group.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclicor bicyclic hydrocarbon ring system having three to eight carbon atomsand zero heteroatom. Examples of monocyclic ring systems includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. The cycloalkyl groups of the present invention can beunsubstituted or substituted, and are connected to the parent moleculamoiety through any substitutable carbon atom of the group.

The term “heterocycle” as used herein, refers to a monocyclic orbicyclic, non-aromatic, saturated or partially unsaturated ring system.Monocyclic ring systems are exemplified by any 4-membered ringcontaining a heteroatom independently selected from oxygen, nitrogen andsulfur; or a 5-, 6-, 7-, or 8-membered ring containing one, two or threeheteroatoms wherein the heteroatoms are independently selected fromnitrogen, oxygen and sulfur. The 5-membered ring has 0 or 1 double bond.The 6-membered ring has 0, 1 or 2 double bonds. The 7- or 8-memberedring has 0, 1, 2 or 3 double bonds. Representative examples ofmonocyclic ring systems include, but are not limited to, azetidinyl,azepanyl, azepinyl, diazepinyl, diazepanyl, dioxolanyl, dioxanyl,dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,3-oxo-morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,2-oxo-oxazolinyl, oxazolidinyl, piperazinyl, piperidyl, pyranyl,pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuryl,tetrahydropyranyl, tetrahydropyridyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl,1,4-diazepanyl and trithianyl. Bicyclic ring systems are exemplified byany of the above monocyclic ring systems fused to a phenyl group, amonocyclic cycloalkenyl group, as defined herein, a monocycliccycloalkyl group, as defined herein, or an additional monocyclicheterocycle group, as defined herein. Representative examples ofbicyclic ring systems include but are not limited to, benzodioxinyl,benzopyranyl, benzothiopyranyl, 2,3-dihydroindolyl, indolizinyl,pyranopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiopyranopyridinyl, 2-oxo-1,3-benzoxazolyl, 3-oxo-benzoxazinyl,3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl,octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, andoctahydropyrrolo[3,4-c]pyrrolyl. The monocyclic or bicyclic ring systemsas defined herein may have two of the non-adjacent carbon atomsconnected by a heteroatom selected from nitrogen, oxygen or sulfur, oran alkylene bridge of between one and three additional carbon atoms.Representative examples of monocyclic or bicyclic ring systems thatcontain such connection between two non-adjacent carbon atoms include,but not limited to, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.2]nonyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 3,4-diazabicyclo[3.2.0]heptyl,2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl,3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-oxazepanyl, 1,4-diazabicyclo[3.2.2]nonyl,1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl,or 8-oxa-3-azabicyclo[3.2.1]octyl, octahydro-1H-4,7-methanoisoindolyl,(3aR,7a5)octahydro-2H-4,7-epoxyisoindolyl andoctahydro-1H-4,7-epoxyisoindolyl. The heterocycle groups of theinvention are substituted or unsubstituted, and are connected to theparent molecular moiety through any substitutable carbon or nitrogenatom in the groups. The nitrogen heteroatom may or may not bequaternized, and may or may not be oxidized to the N-oxide. In addition,the nitrogen containing heterocyclic rings may or may not beN-protected.

The term “heteroaryl” as used herein, refers to an aromatic five- orsix-membered ring where at least one atom is selected from the groupconsisting of N, O, and S, and the remaining atoms are carbon. The fivemembered rings have two double bonds, and the six membered rings havethree double bonds. The term “heteroaryl” also includes bicyclic systemswhere a heteroaryl ring is fused to a phenyl group, a monocycliccycloalkyl group, as defined herein, a heterocycle group, as definedherein, or an additional heteroaryl group. Representative examples ofheteroaryl groups include, but not limited to, benzothienyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl, 4,5-dibenzofuranyl,6,7-dibenzofuranyl, 6,7-dihydro-1,3-benzothiazolyl, furyl, imidazolyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoxazolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl,pyridoimidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl,triazolyl, thiadiazolyl, tetrazolyl,1,2,3,4-tetrahydro-1,8-naphthyridine, 5,6,7,8-tetrahydroquinoline2,3-dihydrospiro[indene-1,4-piperidine]amine, and triazinyl. Theheteroaryl groups of the present invention can be substituted orunsubstituted, and are connected to the parent molecular moiety throughany substitutable carbon or nitrogen atom in the groups. In addition,the nitrogen heteroatom may or may not be quaternized, and may or maynot be oxidized to the N-oxide. Also, the nitrogen containing rings mayor may not be N-protected.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in T. H. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).N-protecting groups comprise acyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like;sulfenyl groups such as phenylsulfenyl (phenyl-S—),triphenylmethylsulfenyl(trityl-S—) and the like; sulfinyl groups such asp-methylphenylsulfinyl (p-methylphenyl-S(O)—), t-butylsulfinyl(t-Bu-S(O)—) and the like; carbamate forming groups such asbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl,4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl,cyclopentyloxycarbonyl, adamantyl-oxycarbonyl, cyclohexyloxycarbonyl,phenylthiocarbonyl and the like; alkyl groups such as benzyl,p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like;p-methoxyphenyl and the like; and silyl groups such as trimethylsilyland the like. Preferred N-protecting groups include formyl, acetyl,benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl,t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term “treating” as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition, orone or more symptoms of such disorder or condition to which such termapplies. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

A “patient” is any individual treated with a compound of the presentinvention, or a therapeutically acceptable salt, solvate, prodrug, orsalt of a prodrug, as defined herein. Patients include humans, as wellas other animals such as companion animals (e.g. dogs and cats) andlivestock. Patients may be experiencing one or more symptoms of acondition responsive to P2X₇ modulation (e.g. pain, inflammation,arthritis), or may be free of such symptom(s) (i.e. treatment may beprophylactic).

This invention is intended to encompass compounds having Formula (I) or(II), when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesincludes those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

The compounds of the invention can comprise asymmetrically substitutedcarbon atoms known as chiral centers. These chiral centers aredesignated as “R” or “S” depending on the configuration of substituentsaround the chiral carbon atom. The terms “R” and “S” used herein areconfigurations as defined in IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. Thecompounds of this invention may exist as single stereoisomers (e.g.,single enantiomers or single diastereomer), mixtures of stereoisomers(e.g. any mixture of enantiomers or diastereomers) or racemic mixtures.All such single stereoisomers, mixtures and racemates are intended to beencompassed within the scope of the invention. Compounds identifiedherein as single stereoisomers are meant to describe compounds that arepresent in a form that are substantially free from their enantiomers orother diastereomers. By “substantially free” is meant greater than about80% free of other enantiomers or diastereomers of the compound, morepreferably greater than about 90% free of other enantiomers ordiastereomers of the compound, even more preferably greater than about95% free of other enantiomers or diastereomers of the compound, evenmore highly preferably greater than about 98% free of other enantiomersor diastereomers of the compound and most preferably greater than about99% free of other enantiomers or diastereomers of the compound. Wherethe stereochemistry of the chiral carbons present in the chemicalstructures illustrated herein is not specified, the chemical structureis intended to encompass compounds containing either stereoisomer ofeach chiral center present in the compound.

Individual stereoisomers of the compounds of this invention can beprepared by any one of a number of methods which are within theknowledge of one of ordinary skill in the art. These methods includestereospecific synthesis, chromatographic separation of diastereomers,chromatographic resolution of enantiomers, conversion of enantiomers inan enantiomeric mixture to diastereomers and then chromatographicallyseparating the diastereomers and regeneration of the individualenantiomers, enzymatic resolution and the like.

Stereospecific synthesis involves the use of appropriate optically pure(enantiomerically pure) or substantial optically pure materials andsynthetic reactions which do not cause racemization or inversion ofstereochemistry at the chiral centers. Mixtures of stereoisomers ofcompounds, including racemic mixtures, resulting from a syntheticreaction can often be separated by chromatographic techniques which arewell-known to those of ordinary skill in the art.

Chromatographic resolution of enantiomers can be accomplished on chiralchromatography resins. Chromatography columns containing chiral resinsare commercially available. In practice, the racemate is placed insolution and loaded onto the column containing the chiral stationaryphase. The enantiomers are then separated by HPLC.

Resolution of enantiomers can also be accomplished by converting theenantiomers in the mixture to diastereomers by reaction with chiralauxiliaries. The resulting diastereomers can then be separated by columnchromatography or crystallization/re-crystallization. This technique isespecially useful when the compounds to be separated contain a carboxyl,amino or hydroxyl group that will form a salt or covalent bond with thechiral auxiliary. Chirally pure amino acids, organic carboxylic acids ororganosulfonic acids are especially useful as chiral auxiliaries. Oncethe diastereomers have been separated by chromatography, the individualenantiomers can be regenerated. Frequently, the chiral auxiliary can berecovered and used again.

Enzymes, such as esterases, phosphatases and lipases, can be useful forresolution of derivatives of the enantiomers in an enantiomeric mixture.For example, an ester derivative of a carboxyl group in the compounds tobe separated can be prepared. Certain enzymes will selectively hydrolyzeonly one of the enantiomers in the mixture. Then the resultingenantiomerically pure acid can be separated from the unhydrolyzed ester.

Alternatively, salts of the enantiomers in the mixture can be preparedby any suitable method known in the art, including treatment of thecarboxylic acid with a suitable optically pure base such as, but are notlimited to, alkaloids and phenethylamine, followed by precipitation orcrystallization/re-crystallization of the enantiomerically pure salts.Methods mentioned herein above and other useful methods for theresolution/separation of a mixture of stereoisomers, including racemicmixtures, may be found in “Enantiomers, Racemates, and Resolutions,” J.Jacques et al., 1981, John Wiley and Sons, New York, N.Y., thedisclosure of which is incorporated herein by reference.

The compounds of this invention may possess one or more unsaturatedcarbon-carbon double bonds. All double bond isomers, both the cis (Z)and trans (E) isomers, and mixtures thereof are intended to beencompassed within the scoped of the present invention. Where a compoundexists in various tautomeric forms, a recited compound is not limited toany one specific tautomer, but rather is intended to encompass alltautomeric forms.

The term “therapeutically acceptable salt” or “pharmaceuticallyacceptable salt” is intended to describe a salt or zwitterions of acompound of the invention and retains the biological effectiveness ofthe free acid or base of the specified compound without undue toxicity,irritation, and allergic response, commensurate with a reasonablebenefit/risk ratio, effective for their intended use and is notbiologically or otherwise undesirable; and as used herein, the term“therapeutically acceptable salt” or “pharmaceutically acceptable salt”refers to salts that are well known in the art. For example, S. M Bergeet al. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:p 1-19, 1977).

The invention also relates to acid addition salts of Formula (I) orFormula (II). If an inventive compound contains a basic moiety a desiredsalt may be prepared by any suitable method known in the art, includingtreatment of the free base with an inorganic acid such as, but are notlimited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, and phosphoric acid, or with an organic acid such as, but are notlimited to, acetic acid, trichloroacetic acid, trifluoroacetic acid,maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid,pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidylacid such as glucuronic acid or galacturonic acid, alpha-hydroxy acidsuch as citric acid or tartaric acid, amino acid such as aspartic acidor glutamic acid, aromatic acid such as benzoic acid or cinnamic acid,sulfonic acid such as p-toluenesulfonic acid, methanesulfonic acid,ethanesulfonic acid or the like. Examples of therapeutically acceptablesalts include acetates, acrylates, adipates, alginates, aspartates,benzenesulfonates, benzoates, bisulfates, bisulfites, bromides,butyne-1,4-dioates, butyrates, camphorates, camphorsulfonates,caproates, caprylates, chlorides, chlorobenzoates, citrate, decanoates,digluconate, dinitrobenzoates, formates, fumarates, glutamates,glycerophosphate, glycollates, hemisulfate, heptanoates, hexanoates,hexyne-1,6-dioates, hydroxybenzoates, γ-hydroxybutyrates, iodides,isethionate, isobutyrates, lactates, mandelates, malonates, maleates,methanesulfonates, methoxybenzoates, methylbenzoates,naphthylenesulfonate, nicotinates, oxalates, pamoates, pectinates,persulfates, phenylacetates, phenylbutyrates, phenylpropionates,phthalates, phosphates, picrates, pivalates, propanesulfonates,propionates, propiolates, p-toluenesulfonates, pyrosulfates, sebacates,suberates, succinates, sulfates, sulfites, tartrates, trichloroacetates,trifluoroacetates, undecanoates, and the like. Also, the basicnitrogen-containing groups can be quaternized with such agents as acidssuch as hydrochloric acid, hydrobromic acid, trifluoroacetic acid oracetic acid, loweralkyl halides, such as methyl, ethyl, propyl, andbutyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl,diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

Compounds of the present invention may contain an acid moiety such as acarboxyl group, it is understood that the invention also encompasses thebase addition salts. Such a desired salt may be prepared by any suitablemethod known to the art, including treatment of the free acid with aninorganic or organic base, such as amine (primary, secondary, ortertiary), an alkali metal or alkaline earth metal hydroxide,carbonates, bicarbonates or the like. Illustrative examples of suitablesalts include organic salts derived from amino acids such as glycine andarginice, ammonia, primary, secondary, and tertiary amines, and cyclicamines, such as ethylene diamine, dicyclohexylamine, ethanolamine,piperidine, morpholine, and piperazine, as well as inorganic saltsderived from sodium, calcium, potassium, magnesium, manganese, iron,copper, zinc, aluminum, and lithium.

In addition, solvates of the compounds of Formula (I) or Formula (II)are meant to be included in this invention. The term “solvate” isintended to mean a pharmaceutically acceptable solvate form of aspecified compound that retains the biological effectiveness of suchcompound. Examples of solvates include compounds of the invention incombination with water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine. In the case of compounds, salts,or solvates that are solids, it is understood by those skilled in theart that the inventive compounds, salts, or solvates may exist isdifferent crystal forms, all of which are intended to be within thescope of the present invention.

This invention also encompasses pharmaceutical compositions containingand methods of treating or preventing comprising administering prodrugsor salt of a prodrug of compounds having Formula (I) or Formula (II).The term “prodrug” are considered to be any covalently bonded carrierswhich release the active parent drug of formula (I) or (II) in vivometabolically or by solvolysis when such prodrugs is administered to amammalian subject. Prodrugs of the compounds of formula (I) or (II) canbe prepared by modifying functional groups present in the compounds insuch a way that the modifications are cleaved, either in routinemanipulation or in vivo, to the parent compounds respectively. Examplesof such modification include, but not limited to, treatment of acompound of formula (I) or (II), containing an amino, amido, or hydroxylmoiety with a suitable derivatising agent, for example, a carboxylicacid halide or acid anhydride, or treatment of a compound of formula (I)or (II) containing a carboxyl moiety, to an ester, amide, carbonates orcarbamates, or conversion of a compound of formula (I) or (II),containing a carboxylic acid ester moiety to an enol-ester. Compounds ofFormula (I) or (II) having free amino, hydroxyl or carboxylic groups canalso be converted to prodrugs by peptide bond formation with an aminoacid residue, or a polypeptide chain of two or more (e.g. two, three orfour) amino acid residues. The amino acid residues include the 20naturally occurring amino acids commonly designated by three letterssymbols and also include, 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithineand methionine sulfone. Prodrugs include, but are not limited to,compounds of Formula (I) or (II) wherein hydroxy, amine, carboxy, orsulfhydryl groups are covalently bonded to any group that, whenadministered to a mammalian subject, cleaves under physiologicalconditions to form a free hydroxyl, amino, carboxy, or sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate, and benzoate derivatives of the hydroxy, carboxy andamine functional groups in the compounds of formula (I) or (II). Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and inEdward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, hereby incorporatedby reference.

In accordance with methods of treatment and pharmaceutical compositionsof the invention, the compounds of formula (I) or (II), ortherapeutically acceptable salt, solvate, prodrug or salt of a prodrugthereof, can be administered alone or be administered in the form of apharmaceutical composition in which the compound of Formula (I) orFormula (II), or a therapeutically acceptable salt, solvate, prodrug,salt of a prodrug, or combination thereof, in combination with apharmaceutically acceptable carriers, adjuvants, diluents, vehicles, orcombinations thereof.

The term “pharmaceutically acceptable carrier, adjuvants, diluents orvehicles” as used herein, means a non-toxic, inert solid, semi-solid orliquid filler, diluent, encapsulating material or formulation auxiliaryof any type. Some examples of materials which can serve aspharmaceutically acceptable carriers are sugars such as lactose, glucoseand sucrose; starches such as corn starch and potato starch; celluloseand its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as cocoa butter and suppository waxes; oils suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols; such a propylene glycol; esters suchas ethyl oleate and ethyl laurate; agar; buffering agents such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol, and phosphatebuffer solutions, as well as other non-toxic compatible lubricants suchas sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention can be formulated in aconventional manner using one or more of the aforementionedpharmaceutically acceptable carriers. Thus the compounds of the presentinvention, its therapeutically acceptable salt, solvate, prodrug, saltof its prodrug, may be administered to humans and other mammals in solidor liquid form, orally, rectally, parenterally, intracisternally,intravaginally, topically (as by powders, ointments, drops, inhalants,spray, transdermal patch, and the like), or bucally. The term“parenterally,” as used herein, refers to modes of administration whichinclude intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle. Suspensions, in addition to the activecompounds, may contain suspending agents, as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of thepresent invention can be incorporated into slow-release ortargeted-delivery systems such as polymer matrices, liposomes, andmicrospheres. They may be sterilized, for example, by filtration througha bacteria-retaining filter or by incorporation of sterilizing agents inthe form of sterile solid compositions, which may be dissolved insterile water or some other sterile injectable medium immediately beforeuse.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more excipients as noted above. The soliddosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings, releasecontrolling coatings and other coatings well known in the pharmaceuticalformulating art. In such solid dosage forms the active compound can beadmixed with at least one inert diluent such as sucrose, lactose, orstarch. Such dosage forms may also comprise, as is normal practice,additional substances other than inert diluents, e.g., tabletinglubricants and other tableting aids such a magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills,the dosage forms may also comprise buffering agents. They may optionallycontain opacifying agents and can also be of such composition that theyrelease the active ingredient(s) only, or preferentially, in a certainpart of the intestinal tract in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin); f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; absorbents such as kaolin and bentonite clay;and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Compounds of the present invention may also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the natural andsynthetic phospholipids and phosphatidylcholines (lecithins) usedseparately or together. Methods to form liposomes are known in the art.See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV,Academic Press, New York, N.Y., (1976), p 33 et seq.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in therapeutically acceptablesalt, solvate, ester, amide, prodrug, salt of a prodrug, or combinationthereof. Alternatively, the compound can be administered as apharmaceutical composition containing a therapeutical effective amountof the compound of present invention, or a therapeutically acceptablesalt, solvate, ester, amide, prodrug, salt of a prodrug, or combinationthereof, in combination with one or more pharmaceutically acceptableexcipients. The phrase “therapeutically effective amount” of thecompound of the invention means a sufficient amount of the compound totreat disorders, at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present invention will bedecided by the attending physician within the scope of sound medicaljudgement. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated; the treatment desired; the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts. Forexample, it is well within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved.

The total daily dose of the compounds having Formula (I) or Formula(II), or a therapeutically acceptable salt, solvate, prodrug, or salt ofa prodrug, administered to a human or other mammal may range from about0.003 to about 50 mg/kg/day. For purposes of oral administration, morepreferable doses can be in the range of from about 0.01 to about 10mg/kg/day. If desired, the effective daily dose can be divided intomultiple doses for purposes of administration; consequently, single dosecompositions may contain such amounts or submultiples thereof to make upthe daily dose.

One of ordinary skill in the art will appreciate that the compounds ofthe invention are useful in treating a diverse array of diseases. One ofordinary skill in the art will also appreciate that when using thecompounds of the invention in the treatment of a specific disease thatthe compounds of the invention may be combined with various existingtherapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies (such as Remicade, CDP-870 and Humira)and TNF receptor immunoglobulin molecules (such as Enbrel®), or COX-2inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib andetoricoxib).

The compounds of the present invention may also be used in combinationwith existing therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents such as piroxicam, diclofenac, propionic acidssuch as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen,fenamates such as mefenamic acid, indomethacin, sulindac, apazone,pyrazolones such as phenylbutazone, salicylates such as asprin, COX-2inhibitors such as celecoxib, valdecoxib, rofecoxib and etoricoxib,analgesics and intraarticular therapies such as corticosteroids andhyaluronic acids such as hyalgan and synvisc.

The compounds of the present invention may also be used in combinationwith CNS agents such as antidepressants (such as sertraline),anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOBinhibitors such as selegine and rasagiline, comp inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,Nicotine agonists, dopamine agonists and inhibitors or neuronal nitricoxide synthase), and anti-Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metrifonate.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, droloxifene, lasofoxifeneor fosomax.

The compounds of the present invention may also be used in combinationwith immunosuppressant agents such as FK-506, rapamycin, cyclosporine,azathioprine, and methotrexate.

Synthetic Methods

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: DMSO is dimethylsulfoxide and THF istetrahydrofuran.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. The groups A, B, E, Z, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, m and v are as defined above unless otherwise noted below.

Compounds of the invention may be prepared by a variety of syntheticroutes. Representative procedures are described in Scheme 1 as shownbelow:

Aminotetrazoles can be prepared by a variety of procedures. Examples ofsuch construction can be found in Atherton, F. R.; Lambert, R. W.,Tetrahedron 1983, 39, 2599-2608, Imhof, R.; Ladner, D. W.; Muchowski, J.M. J. Org. Chem. 1977, 42, 3709-3713, or Robert A. Batey and David A.Powell, Org. Lett. 2000, 2, 3237-3240. In particular, aminotetrazoles offormula (I) can be prepared from thioureas of formula (1), an azidereagent and mercury (II) salts, in the presence or absence of a base,and in a solvent such as, but not limited to, tetrahydrofuran,N,N-dimethylformamide, acetonitrile, 1,4-dioxane and methanol. Examplesof the azide reagents include, but are not limited to, sodium azide andtrimethylsilyl azide. Examples of the mercury (II) salts include, butare not limited to, mercury (II) chloride, mercury (II) bromide, mercury(II) iodide and mercury (II) acetate. Examples bases include, but arenot limited to, triethylamine, diisopropylethyl amine, pyridine,4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassiumcarbonate and N-methylmorpholine. The thioureas of formula (1) can bepurchased commercially or prepared from amines of formula (4) andisothiocyanates of formula (3) in a solvent such as, but are not limitedto, dichloromethane, tetrahydrofuran, chloroform, diethylether,acetonitrile, 1,4-dioxane, N,N-dimethylformamide and toluene. Theresulting thioureas can be used in situ or purified and isolated.Compounds of Formula (II) may be prepared similarly.

Alternatively, compounds of formula (I) wherein R², X, Y, Z, m, and R¹are as defined in formula (1) can also be prepared from compounds offormula (5) as shown in Scheme 2.

Compounds of formula (5) wherein R² is as defined in formula (I) can beprepared as described in Kuehle, Engelbert; Anders, Bertram, Zumach andGerhard; Angewandte Chemie (1967), 79(15), 663-80. Chloro-tetrazoles offormula (6) can be obtained from the reaction of compounds of formula(5) with an azide reagent such as, but not limited to, sodium azide, andtetrabutyl ammonium bromide. The reaction is generally conducted in amixture of solvents such as, but not limited to, toluene/water,benzene/water, dichloromethane/water or xilene/water.

Displacement of the chloro-tetrazoles of formula (6) with amines offormula (4) can be achieved in the presence of a base such as, but notlimited to, triethylamine. The reaction is generally conducted in asolvent such as, but not limited to, tetrahydrofuran, dioxane or1,2-dimethoxyethane at a temperature from about room temperature toabout 150° C.

Compounds of formula (II) can also be prepared similarly.

Amines of formula (4) wherein Z is hydrogen, and X, Y, m and R¹ are asdefined in formula (I), can be prepared from alcohols of formula (7) asshown in Scheme 3. Alcohols of formula (7) can be reacted with neatthionyl chloride or using a solvent such as, but not limited to,dichloromethane or chloroform to provide chlorides of formula (8).Displacement of chlorides of formula (8) with sodium azide in a solventsuch as, but not limited to, N,N-dimethylformamide or acetone, providesazides of formula (9), which can be reduced to amines of formula (4) inthe presence of a reducing agent such as, but not limited to,palladium/carbon or PtO₂/carbon. The reaction can be performed in asolvent such as, but not limited to, ethanol, methanol or ethyl acetate.

Amines of formula (4) wherein X, Y and Z are hydrogen and m is 1, can beprepared from the corresponding aldehydes of formula (10) as depicted inScheme 4. Reaction of the aldehydes of formula (10) with hydroxylaminehydrochloride in an alcoholic solvent such as, but not limited to,ethanol, provides oximes of formula (11). Oximes of formula (11) can beconverted to nitrites of formula (12) in the presence of aceticanhydride and a base such as, but not limited to, potassium hydroxide orsodium hydroxide. Reduction of the nitriles of formula (12) withRaney/nickel and ammonia can be performed in an alcoholic solvent suchas, but not limited to, methanol.

Nitriles of formula (12) wherein R¹ is aryl or heteroaryl can beprepared by displacement of an the corresponding bromides with zinccyanide in the presence of a palladium catalyst, such as but not limitedto, bis(triphenylphosphine)palladium (II) chloride and in a solvent suchas N,N-dimethylformamide.

Certain ether-containing arylnitriles of formula (14) wherein R hydrogenor the substituents of R¹ of formula (I) and R^(1e) is as defined informula (I), can be prepared by reaction of a hydroxybenzonitriles offormula (13) with halides of formula (15) wherein X is fluoro or chloro,in the presence of a base such as, but not limited to, sodium hydride orpotassium carbonate. The reaction can be conducted in a solvent such astetrahydrofuran, dimethylformamide or dioxane at a temperature fromabout room temperature to about 150° C.

Nicotinonitriles of formula (17) with an ether linkage in the 2-positionwherein R^(1e) is as defined in formula (I), and R is hydrogen or thesubstitutent of R¹ in formula (I), can be prepared by reaction ofoptionally substituted 2-fluoronicotinonitriles of formula (16), withalcohols of formula (18) in the presence of a base such as sodiumhydride or potassium carbonate. The reaction can be conducted in asolvent such as tetrahydrofuran, dimethylformamide or dioxane at atemperature from about room temperature to about 150° C.

Nicotinonitriles of formula (19) with an amino linkage in the2-position, wherein R_(x) and R_(y) are independently selected from thegroup consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl andheterocycle and R^(X) is hydrogen or the same as the substituent of R¹of formula (I), can be prepared by reaction of optionally substituted2-fluoronicotinonitriles of formula (16) with an appropriate primary orsecondary amine of formula (20), in the presence of a base such assodium hydride or potassium carbonate. The reaction can be conducted ina solvent such as tetrahydrofuran, dimethylformamide or dioxane at atemperature from about room temperature to about 150° C.

Nicotinonitriles of formula (22) wherein R¹ is hydrogen or the same asthe substituents of R¹ in formula (I) and R^(1c) is as defined informula (I), can be prepared by reaction of nitriles of formula (21)wherein X is Cl, Br, I or triflate with an appropriate boronic acid orester of formula (23) wherein R₁₀₁ is hydrogen or alkyl, in the presenceof a palladium catalyst, such as but not limited to,bis(triphenylphosphine)palladium (II) chloride and a base such astriethylamine or sodium carbonate. The reaction can be effected byheating from 50-90° C. in solvents such as isopropanol, ethanol,dimethoxyethane, water or dioxane. Alternatively, this transformationcan be accomplished using an tin reagent of formula (24) wherein R₁₀₂ isalkyl, with a palladium catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), and cesium fluoride andheating in a solvent such as dioxane. These transformations can also beeffected by heating in a microwave reactor.

Alcohols of formula (7) where R¹ is a substituted thiazole can beprepared as shown in Scheme 10. The aldehyde of formula (25) can bereduced with sodium borohydride then protected as thet-butyldimethylsilyl ether, followed by mono-debromination with n-butyllithium. The mono-bromothiazole of formula (27) can then be reacted withboronic acid of formula (23) using a palladium catalyst such as but notlimited to, bis(triphenylphosphine)palladium (II) chloride, and a basesuch as triethylamine or sodium carbonate with heating from 50-90° C. ina solvent such as isopropanol or dioxane. Solvent mixtures ofdimethoxyethane, water and ethanol can also be used. Alternatively, thistransformation can be accomplished using tin reagent of formula (24), apalladium catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), and cesium fluoride andheating in a solvent such as dioxane. These transformations can also beeffected by heating in a microwave reactor.

Amines of formula (31) wherein A is the ring as represented as R¹ offormula (I), R is hydrogen or the same as the substituents of R¹ informula (I), and X, Y, m and R^(1c) are as defined in formula (I), canbe prepared as shown in Scheme 11. The N-boc protected boronic acid offormula (29) wherein G is B(OH)₂ can be reacted with compounds offormula (32) wherein X is Cl, I, Br, or triflate, in the presence of apalladium catalyst, such as but not limited to,bis(triphenylphosphine)palladium (II) chloride, and a base such astriethylamine or sodium carbonate. The reaction can be effected byheating from 50-90° C. and is generally conducted in a solvent such as,but not limited to, isopropanol or dioxane. Solvent mixtures ofdimethoxyethane, water and ethanol can also be used. Alternatively, thistransformation can be accomplished using tin reagent of formula (29)wherein G is Sn(alkyl)₃ in the presence of a palladium catalyst such as,but not limited to, tetrakis(triphenylphosphine)palladium(0), and cesiumfluoride. The reaction is generally effected by heating and performed ina solvent such as dioxane. These transformations can also be effected byheating in a microwave reactor. The N-boc protecting group can beremoved by reaction with an acid such as, but not limited to,trifluoroacetic acid or hydrochloric acid in a solvent such asdichloromethane or ether.

To a solution of amine (A) (80 mg, 0.183 mmol) in dimethylformamide (2ml) was added potassium carbonate (51 mg, 0.366 mmol) and alkylbromide(B) (0.220 mmol). The reaction mixture was stirred at room temperaturefor 16 hours then poured onto ice water. The aqueous mixture wasextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated. The residue waspurified by flash column chromatography or preparative HPLC on aThermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size)using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM)over 20 minutes at a flow rate of 21 mL/min to provide the titlecompound.

To a solution of amine (A) (80 mg, 0.183 mmol) in dichloromethane (3 ml)was added triethylamine (0.2 mL) and acylating reagent (C) (0.366 mmol).The reaction mixture was stirred at room temperature for 2 hours.Saturated sodium carbonate was added and the layers were separated. Theaqueous mixture was extracted with dichloromethane. The organic layerwas washed with brine, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography orpreparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2mm., 8 μm particle size) using a gradient of 5% to 75% acetonitrile toammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min toprovide the title compound.

To an oven-dried, N₂-purged, 50-mL, round-bottomed flask containing amagnetic stir bar were added the commercially available2-fluoro-3-cyanopyridine (216 mg, 1.77 mmol), the arylhydroxide (D)(1.77 mmol), anhydrous potassium carbonate (318 mg, 2.30 mmol) andanhydrous acetonitrile (10 mL). The reaction mixture was stirred for 18hours at ambient temperature. The insoluble material was removed byfiltration and the solvent was removed from the filtrate in vacuo togive the 2-aryloxy-nicotinonitrile.

Determination of Biological Activity

Tissue Culture: Cells of the THP-1 monocytic cell line (American TypeCulture Collection, Rockville, Md.) were maintained in the log phase ofgrowth in RPMI medium containing high glucose and 10% fetal calf serum(Invitrogen, Carlsbad, Calif.) according to established procedures(Humphrey B D and Dubyak G R (1996), Induction of the P2z/P2X7Nucleotide Receptor and Associated Phospholipase D Activity byLipopolysaccharide and IFN-γ in the Human THP-1 Monocytic Cell Line. J.Immunology 157:5627-37). Fresh vials of frozen THP-1 cells wereinitiated for growth every eight weeks. To differentiate THP-1 cellsinto a macrophage phenotype, a final concentration of 25 ng/ml oflipopolysaccharide (LPS) and 10 ng/ml of IFNγ were added to the cellseither for 3 hours for IL-1β release assays or overnight (16 hours) forpore formation studies.

P2X₇ Mediated Pore Formation. Activation of the P2X₇ receptor inducesnonspecific pore formation and eventually cell lysis (Verhoef et al.,The Journal of Immunology, Vol. 170, pages 5728-5738, 2003).Accordingly, the inhibitory activity of the antagonists of the presentinvention was determined by their capacity to inhibit theagonist-induced pore formation using the fluorescent dye YO-PRO (MW=629)and Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices,Sunnydale, Calif.). Prior to YO-PRO dye addition, the cells were rinsedonce in PBS without Mg²⁺ or Ca²⁺ ions, which have been shown to inhibitpore formation (Michel et al., N—S Arch Pharmacol 359:102-109, 1999).The YO-PRO iodide dye (1 mM in DMSO) was diluted to a finalconcentration of 2 μM in phosphate buffered saline (PBS without Mg²⁺ orCa²⁺) and then placed on the cells prior to the addition of the agonistBzATP. Since the THP-1 cells are a non-adherent cell line, the cellswere washed in PBS and loaded with the dye in a conical tube prior tospinning the cells onto poly-lysine-coated black-walled 96-well plates,which were utilized to reduce light scattering. After the addition ofthe agonist BzATP (50 μM, the EC₇₀ value for agonist activation), theYO-PRO dye uptake was observed in the FLIPR apparatus equipped with anArgon laser (wavelength=488 nm) and a CCD camera. The intensity of thefluorescence was captured by the CCD camera every 15 seconds for thefirst 10 minutes of agonist exposure followed by every 20 seconds for anadditional 50 minutes with the data being digitally transferred to aninterfaced PC. The exposure setting of the camera was 0.25 sec with anf-stop setting of 2. Solutions of antagonist compounds were prepared byserial dilutions of a 10 mM DMSO solution of the antagonist into thebuffer solution with the YO-PRO dye. Antagonist compounds were testedfor activity over a concentration range from 0.003 to 100 μM. The testcompounds were incubated for 10 minutes with the THP-1 cells at roomtemperature, after which the cells were stimulated with BzATP andfluorescence measured as described above in the absence of theantagonist. For antagonist activity measurements, the percent maximalintensity was normalized to that induced by 50 μM BzATP and plottedagainst each concentration of compound to calculate IC₅₀ values andaccount for plate-to-plate variability.

The potency of the compounds was inversely proportional to their IC₅₀value. Representative compounds of the present invention when testedwith the above assay demonstrated antagonist activity at the P2X₇receptor.

P2X₇ Mediated IL-1β Release: Activation of P2X7 receptors also inducessecretion of IL-1β (Verhoef et al., above; Brough et al., Molecular andCellular Neuroscience, Vol. 19, pages 272-280, 2002). THP-1 cells wereplated in 24-well plates at a density of 1×10⁶ cells/well/ml. On the dayof the experiment, cells were differentiated with 25 ng/ml LPS and 10ng/ml final concentration of γIFN for 3 hours at 37° C. Solutions ofantagonist compounds were prepared by serial dilutions of a 10 mM DMSOsolution of the antagonist into the PBS solution. In the presence of thedifferentiation media, the cells were incubated with the antagonists ofthe present invention for 30 minutes at 37° C. followed by a challengewith 1 mM BzATP for an additional 30 minutes at 37° C. Supernatants ofthe samples were collected after a 5 minute centrifugation in microfugetubes to pellet the cells and debris and to test for mature IL-1released into the supernatant using either R & D Systems Human IL-1βELISA assay or Endogen Human IL-1β ELISA, following the manufacturer'sinstructions. The maximum IL-1β release at each concentration of testcompound was normalized to that induced by BzATP alone to determine theactivity of the test compound. Antagonist compounds were tested foractivity over a concentration range from 0.001 to 100 μM. Antagonistpotency was expressed as the concentration producing a 50% reduction inrelease of IL-1β or IC₅₀. For each experiment, differentiated controlcells were also measured over the 60 min time course of the assay toassess background IL-1β accumulation. This non-specific background IL-1Drelease, typically averaged 3-8% of the maximum BzATP response, wassubtracted from the maximum BzATP-induced release and all release valuesnormalized to the BzATP-induced response. Representative compounds ofthe present invention when tested with the above assay demonstratedantagonist activity at the P2X₇ receptor.

For all in vitro experiments, compounds of the present invention hadIC₅₀ lower than 10 μM, preferably lower than 0.5 μM, and most preferablylower than 0.05 μM.

Determination of Analgesic Activity

Adult male Sprague-Dawley rats (250-300 g), Charles River Laboratories,Portage, Mich. were used in this study. Animal handling and experimentalprotocols were approved by the Institutional Animal Care and UseCommittee (IACUC) at Abbott Laboratories. For all surgical procedures,animals were maintained under halothane anesthesia (4% to induce, 2% tomaintain), and the incision sites were sterilized using a 10%povidone-iodine solution prior to and after surgeries.

Spinal Nerve ligation: A model of spinal nerve ligation-inducedneuropathic pain was produced using the procedure originally describedby Kim and Chung (Kim and Chung, Pain, Vol. 50 pages 355-363, 1992). Theleft L5 and L6 spinal nerves of the rat were isolated adjacent to thevertebral column and tightly ligated with a 5-0 silk suture distal tothe DRG, and care was taken to avoid injury of the L4 spinal nerve. Shamrats underwent the same procedure, but without nerve ligation. Allanimals were allowed to recover for at least 1 week and not more than 3weeks prior to assessment of mechanical allodynia. Mechanical allodyniain the left hind paw was confirmed by comparing the paw withdrawalthreshold in grams for the injured left paw and the uninjured right paw.Mechanical allodynia was measured using calibrated von Frey filaments(Stoelting, Wood Dale, Ill.). Rats were placed into inverted individualplastic containers (20×12.5×20 cm) on top of a suspended wire mesh grid,and acclimated to the test chambers for 20 min. The von Frey filamentswere presented perpendicularly to the plantar surface of the selectedhind paw, and then held in this position for approximately 8 sec withenough force to cause a slight bend in the filament. Positive responsesincluded an abrupt withdrawal of the hind paw from the stimulus, orflinching behavior immediately following removal of the stimulus. A 50%withdrawal threshold was determined using an up-down procedure (Dixon,Ann. Rev. Pharmacol. Toxicol., Vol. 20, pages 441-462, 1980). Prior tocompound administration, animals demonstrating motor deficit or failureto exhibit subsequent mechanical allodynia were excluded from furtherstudies. The antinociceptive activity of a test compound was determinedby comparing its ability to increase the paw withdrawal threshold of theinjured left paw relative to vehicle (0%) and the uninjured right paw(100%). Activity of test compounds was determined 60 minutes after anoral dose or 30 minutes after an intraperitoneal dose. Dose-responsecurves as well as single dose responses were performed. Representativecompounds of the present invention exhibited antinociceptive activity inthis assay.

C Freund's adjuvant-induced thermal hyperalgesia: Unilateralinflammation was induced by injecting 150 μl of a 50% solution ofcomplete Freund's adjuvant (CFA) (Sigma Chemical Co., St. Louis, Mo.) inphysiological saline into the plantar surface of the right hindpaw ofthe rat. The hyperalgesia to thermal stimulation was determined 48 hrafter CFA injections using a commercially available paw thermalstimulator (UARDG, Department of Anesthesiology, University ofCalifornia, San Diego, La Jolla, Calif.). Rats were placed individuallyin Plexiglass cubicles mounted on a glass surface maintained at 30° C.,and allowed a 30 min habituation period. A thermal stimulus, in the formof radiant heat emitted from a focused projection bulb, was then appliedto the plantar surface of each hind paw. The stimulus current wasmaintained at 4.5 Amp and the maximum time of exposure was set at 20 secto limit possible tissue damage. In each test session, each rat wastested in 3 sequential trials at approximately 5 min intervals. Pawwithdrawal latencies were calculated as the mean of the two shortestlatencies. The antinociceptive activity of a test compound wasdetermined by comparing its ability to increase the paw withdrawalthreshold of the injured right paw relative to vehicle (0%) and theuninjured left paw (100%). Activity of test compounds was determined 60minutes after an oral dose or 30 minutes after an intraperitoneal dose.Dose-response curves as well as single dose responses were performed.Representative compounds of the present invention exhibitedantinociceptive activity in this assay.

Zymosan Method: Mice were dosed with experimental compounds orally orsubcutaneously 30 minutes prior to injection of zymosan. Mice were theninjected intraperitonealy with 2 mgs/animal of zymosan suspended insaline. Four hours later the animals were euthanized by CO₂ inhalationand the peritoneal cavities lavaged with 2×1.5 mL of ice cold phosphatebuffered saline containing 10 units of heparin/mL. For IL-1βdetermination the samples were spun at 10,000×g in a refrigeratedmicrofuge (4° C.), supernatants removed and frozen until ELISAs (EnzymeLinked Immuno-Assay) were performed. ELISAs were performed according tomanufacture's instructions. IL-1β was determined relative to vehiclecontrol. Representative compounds of the invention demonstratedinhibition of IL-1β release in a dose-dependent fashion. (Perretti M,Solito E, Parente L, Agents Actions Vol. 35(1-2) pages 71-78, 1992;Torok K, Nemeth K, Erdo F, Aranyi P, Szekely, J I, Inflamm Res. Vol.44(6) pages 248-252, 1995). Representative compounds of this inventionexhibited inhibition of IL-1β release in this assay.

For all in vivo experiments, the compounds of the present invention hadED50 lower than 500 μmol/kg, preferably 50 μmol/kg.

The present invention will now be described in connection with certainpreferred embodiments, which are not intended to limit its scope. On thecontrary, the present invention covers all alternatives, modifications,and equivalents as can be included within the scope of the claims. Thus,the following examples, which include preferred embodiments, willillustrate the preferred practice of the present invention, it beingunderstood that the examples are for the purpose of illustration ofcertain preferred embodiments and are presented to provide what isbelieved to be the most useful and readily understood description of itsprocedures and conceptual aspects.

EXAMPLE 11-(2,3-dichlorophenyl)-N-[(2-methylphenyl)methyl]-1H-tetrazol-5-amine

2-Methylbenzylamine (89.1 mg, 0.735 mmol) in 8 ml of dry THF was treatedwith 2,3-dichlorophenylisothiocyanate (150 mg, 0.735 mmol). Afterstirring at room temperature for 1 hour, the mixture was treated withmercuric acetate (234.2 mg, 0.735 mmol) and sodium azide (143.3 mg, 2.21mmol) and stirred at room temperature for 16 hours. The mixture wasfiltered through a pad of Celite and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure and purified bypreparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μmparticle size) using a gradient of 10% to 100% acetonitrile to ammoniumacetate (10 mM) over 15 minutes at a flow rate of 70 mL/min to providethe title compound. MS (ESI⁺) m/z 334 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.29 (s, 3H), 4.46 (d, J=5.42 Hz, 2H), 7.16 (m, 3H), 7.26 (m, 1H),7.57 (t, J=5.42 Hz, 1H), 7.60 (t, J=8.14 Hz, 1H), 7.71 (dd, J=7.97, 1.53Hz, 1H), 7.93 (dd, J=8.14, 1.70 Hz, 1H).

EXAMPLE 21-(2,3-dichlorophenyl)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (1R)-2,3-dihydro-1H-inden-1-ylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 346 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.90 (m, 1H), 2.53 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 7.22 (m, 4H),7.53 (d, J=9.15 Hz, 1H), 7.57 (t, J=8.14 Hz, 1H), 7.70 (dd, J=9.00, 1.70Hz, 1H), 7.90 (dd, J=9.00, 1.36 Hz, 1H).

EXAMPLE 31-(2,3-dichlorophenyl)-N-[(2-morpholin-4-ylphenyl)methyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (2-morpholin-4-ylphenyl)methylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 405 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.83 (m, 4H), 3.71 (m, 4H), 4.59 (d, J=5.76 Hz, 2H), 7.07 (m, 1H),7.14 (dd, J=7.97, 1.19 Hz, 1H), 7.24 (dd, J=7.12, 1.70 Hz, 1H), 7.28 (m,1H), 7.56 (t, J=5.76 Hz, 1H), 7.60 (t, J=7.97 Hz, 1H), 7.72 (dd, J=8.50,1.70 Hz, 1H), 7.94 (dd, J=8.14, 1.70 Hz, 1H).

EXAMPLE 41-(2,3-dichlorophenyl)-N-(pyridin-4-ylmethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using pyridin-4-ylmethylamine instead of 2-methylbenzylamine.MS (ESI⁺) m/z 321 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 4.51 (d, J=5.76Hz, 2H), 7.31 (dd, J=6.00, 1.70 Hz, 2H), 7.64 (t, J=8.14 Hz, 1H), 7.77(dd, J=8.45, 1.36 Hz, 1H), 7.82 (d, J=6.10 Hz, 1H), 7.97 (dd, J=8.45,1.36 Hz, 1H), 8.51 (dd, J=6.00, 1.70 Hz, 2H).

EXAMPLE 51-(2,3-dichlorophenyl)-N-{[2-(dimethylamino)phenyl]methyl}-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 2-(aminomethyl)-N,N-dimethylaniline instead of2-methylbenzylamine. MS (ESI⁺) m/z 363 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.62 (m, 6H), 4.57 (d, J=5.76 Hz, 2H), 7.01 (m, 1H), 7.12 (dd, J=7.97,1.19 Hz, 1H), 7.20 (dd, J=7.29, 1.53 Hz, 1H), 7.26 (m, 1H), 7.59 (t,J=5.76 Hz, 1H), 7.61 (t, J=7.97 Hz, 1H), 7.72 (dd, J=8.45, 1.70 Hz, 1H),7.94 (dd, J=8.14, 1.70 Hz, 1H).

EXAMPLE 61-(2,3-dichlorophenyl)-N-(pyridin-3-ylmethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using pyridin-3-ylmethylamine instead of 2-methylbenzylamine.MS (ESI⁺) m/z 321 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 4.51 (d, J=5.62Hz, 2H), 7.36 (dd, J=7.80, 4.68 Hz, 1H), 7.62 (t, J=8.11 Hz, 1H), 7.72(m, 3H), 7.95 (dd, J=8.27, 1.40 Hz, 1H), 8.46 (dd, J=4.68, 1.56 Hz, 1H),8.55 (d, J=1.87 Hz, 1H).

EXAMPLE 71-(2,3-dichlorophenyl)-N-{[2-(pyridin-2-yloxy)phenyl]methyl}-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using [2-(pyridin-2-yloxy)phenyl]methylamine hydrochloride and1 equivalent of triethylamine instead of 2-methylbenzylamine. MS (ESI⁺)m/z 413 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 4.41 (d, J=5.93 Hz, 2H),7.01 (d, J=8.11 Hz, 1H), 7.07 (dd, J=7.80, 0.94 Hz, 1H), 7.12 (dd,J=7.18, 4.99 Hz, 1H), 7.21 (m, 1H), 7.31 (m, 1H), 7.40 (d, J=7.49 Hz,1H), 7.55 (t, J=5.77 Hz, 1H), 7.59 (t, J=7.80 Hz, 1H), 7.62 (dd, J=4.10,1.87 Hz, 1H), 7.85 (m, 1H), 7.93 (dd, J=7.64, 2.03 Hz, 1H), 8.10 (dd,J=4.84, 2.03 Hz, 1H).

EXAMPLE 81-(2,3-dichlorophenyl)-N-(2-pyridin-2-ylethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 2-pyridin-2-ylethylamine instead of 2-methylbenzylamine.MS (ESI⁺) m/z 335 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.02 (t, J=7.29Hz, 2H), 3.64 (m, 2H), 7.22 (m, 3H), 7.59 (t, J=7.63 Hz, 1H), 7.64 (dd,J=8.50, 2.03 Hz, 1H), 7.69 (m, 1H), 7.93 (dd, J=6.00, 2.37 Hz, 1H), 8.47(m, 1H).

EXAMPLE 91-(2,3-dichlorophenyl)-N-(1-methyl-1-phenylethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-methyl-1-phenylethylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 348 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.67 (s, 6H), 7.19 (t, J=7.17 Hz, 1H), 7.29 (m, 3H), 7.38 (m, 2H),7.63 (t, J=7.91 Hz, 1H), 7.70 (dd, J=8.00, 1.84 Hz, 1H), 7.96 (dd,J=7.91, 1.65 Hz, 1H).

EXAMPLE 101-(2,3-dichlorophenyl)-N-(2-pyridin-3-ylpropyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 2-pyridin-3-ylpropan-1-amine instead of2-methylbenzylamine. MS (ESI⁺) m/z 349 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.18 (d, 3H), 2.83 (m, 2H), 4.00 (m, 1H), 7.02 (d, 1H); 7.28 (dd, 1H),7.60 (m, 3H), 7.94 (m, 1H), 8.39 (m, 2H).

EXAMPLE 111-(2,3-dichlorophenyl)-N-(quinolin-4-ylmethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-quinolin-4-ylmethanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 371 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 5.02 (d, 2H), 7.45 (d, 1H), 7.65 (m, 2H), 7.79 (m, 2H), 7.91 (t, 1H),7.97 (dd, 1H), 8.05 (d, 1H), 8.19 (d, 1H), 8.85 (d, 1H).

EXAMPLE 121-(2,3-dichlorophenyl)-N-(2-pyridin-3-ylethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 2-pyridin-3-ylethanamine instead of 2-methylbenzylamine.MS (ESI⁺) m/z 335 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.89 (t, 2H), 3.52(q, 2H), 7.22 (t, 1H), 7.30 (dd, 1H), 7.62 (m, 3H), 7.93 (dd, 1H), 8.41(m, 2H).

EXAMPLE 131-(2,3-dichlorophenyl)-N-[2-(2-methylphenyl)ethyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 2-(2-methylphenyl)ethanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 348 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.30 (s, 3H), 2.86 (t, 2H), 3.42 (q, 2H), 7.11 (m, 4H), 7.23 (t, 1H),7.58-7.67 (m, 2H), 7.94 (dd, 1H).

EXAMPLE 141-(2,3-dichlorophenyl)-N-[(3-methylpyridin-4-yl)methyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (3-methylpyridin-4-yl)methylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 335 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.28 (s, 3H), 4.48 (d, 2H), 7.21 (d, 1H), 7.63 (t, 1H), 7.74 (t, 1H),7.78 (dd, 1H), 7.97 (dd, 1H), 8.36 (m, 2H).

EXAMPLE 151-(2,3-dichlorophenyl)-N-[(1-methyl-1H-pyrrol-2-yl)methyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (1-methyl-1H-pyrrol-2-yl)methylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 323 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 3.54 (s, 3H), 4.44 (d, 2H), 5.87 (t, 1H), 5.97 (dd, 1H), 6.66 (t, 1H),7.45 (t, 1H), 7.57 (t, 1H), 7.66 (dd, 1H), 7.91 (dd, 1H).

EXAMPLE 16N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-5,6,7,8-tetrahydroquinolin-5-amine

The title compound was prepared using the procedure described in Example1 except using 5,6,7,8-tetrahydroquinolin-5-amine instead of2-methylbenzylamine. MS (ESI⁺) m/z 361 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.75-2.07 (m, 4H), 2.81 (t, 2H), 5.01 (m, 1H), 7.19 (dd, 1H),7.55-7.60 (m, 2H), 7.64 (br d, 1H), 7.71 (dd, 1H), 7.90 (dd, 1H), 8.37(dd, 1H).

EXAMPLE 171-(2,3-dichlorophenyl)-N-[(2-methylthien-3-yl)methyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (2-methylthien-3-yl)methylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 340 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.19 (s, 3H), 4.56 (d, 2H), 6.82 (d, 1H), 7.28 (d, 1H), 7.57-7.72 (m,3H), 7.94 (dd, 1H).

EXAMPLE 181-(2,3-dichlorophenyl)-N-[3-(dimethylamino)benzyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using N-[3-(aminomethyl)phenyl]-N,N-dimethylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 363 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.86 (s, 6H), 4.42 (d, 2H), 6.60 (m, 2H), 6.67 (t, 1H), 7.11 (t, 1H),7.58-7.66 (m, 2H), 7.69 (dd, 1H), 7.94 (dd, 1H).

EXAMPLE 191-(2,3-dichlorophenyl)-N-[2-(4-fluorophenoxy)benzyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-[2-(4-fluorophenoxy)phenyl]methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 430 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 4.52 (d, 2H), 6.82 (d, 1H), 7.02 (m, 2H), 7.13 (td, 1H), 7.19-7.31 (m,3H), 7.41 (dd, 1H), 7.58-7.69 (m, 3H), 7.95 (dd, 1H).

EXAMPLE 201-(2,3-dichlorophenyl)-N-[2-(methylthio)benzyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-[2-(methylthio)phenyl]methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 366 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.48 (s, 3H), 4.49 (d, 2H), 7.15 (m, 1H), 7.26-7.33 (m, 3H), 7.61 (t,1H), 7.65 (t, 1H), 7.73 (dd, 1H), 7.95 (dd, 1H).

EXAMPLE 21 N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-phenylmethanamine instead of 2-methylbenzylamine. MS(ESI⁺) m/z 320 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 4.48 (d, 2H), 7.26(m, 1H), 7.32 (m, 4H), 7.61 (t, 1H), 7.68-7.73 (m, 2H), 7.95 (dd, 1H).

EXAMPLE 221-(2,3-dichlorophenyl)-N-[3-(pyrazin-2-yloxy)benzyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-[3-(pyrazin-2-yloxy)phenyl]methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 414 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 4.51 (d, 2H), 7.08-7.15 (m, 2H), 7.22 (d, 1H), 7.40 (t, 1H), 7.60 (t,1H), 7.70-7.77 (m, 2H), 7.95 (dd, 1H), 8.19 (m, 1H), 8.38 (d, 1H), 8.53(d, 1H).

EXAMPLE 231-(2,3-dichlorophenyl)-N-[2-(1H-pyrrol-1-yl)benzyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-[2-(1H-pyrrol-1-yl)phenyl]methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 385 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 4.35 (d, 2H), 6.24 (t, 2H), 6.99 (t, 2H), 7.25-7.34 (m, 1H), 7.37-7.45(m, 2H), 7.46-7.51 (m, 1H), 7.59-7.64 (m, 2H), 7.71 (dd, 1H), 7.95 (dd,1H).

EXAMPLE 241-(2,3-dichlorophenyl)-N-[4-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-[4-(pyridin-2-yloxy)phenyl]methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 413 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 4.49 (d, 2H), 7.01 (d, 1H), 7.05-7.15 (m, 3H), 7.36 (d, 2H), 7.62 (t,1H), 7.70-7.75 (m, 2H), 7.81-7.87 (m, 1H), 7.95 (dd, 1H), 8.13 (dd, 1H).

EXAMPLE 251-(2,3-dichlorophenyl)-N-[3-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-[3-(pyridin-2-yloxy)phenyl]methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 413 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 4.49 (d, 2H), 7.01 (m, 2H), 7.06 (m, 1H), 7.1-7.2 (m, 2H), 7.36 (t,1H), 7.60 (t, 1H), 7.69 (dd, 1H), 7.72 (t, 1H), 7.82-7.88 (m, 1H), 7.94(dd, 1H), 8.13 (ddd, 1H).

EXAMPLE 261-(2,3-dichlorophenyl)-N-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)methyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (3-methyl-1-phenyl-1H-pyrazol-5-yl)methylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 400 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.19 (s, 3H), 4.53 (d, 2H), 6.21 (s, 1H), 7.42 (m, 1H), 7.46-7.52 (m,4H), 7.59-7.62 (m, 2H), 7.71 (t, 1H), 7.94 (dd, 1H).

EXAMPLE 27 1-(2,3-dichlorophenyl)-N-(2-methylphenyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 2-methylphenylamine instead of 2-methylbenzylamine. MS(ESI⁺) m/z 320 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 3H),7.07-7.25 (m, 3H), 7.30 (dd, 1H), 7.61 (t, 1H), 7.80 (dd, 1H), 7.93 (dd,1H), 8.86 (s, 1H).

EXAMPLE 281-(2,3-dichlorophenyl)-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (1,5-dimethyl-1H-pyrazol-4-yl)methylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 338 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 2.21 (s, 3H), 3.67 (s, 3H), 4.24 (d, 2H), 7.26 (s, 1H), 7.33 (t, 1H),7.58 (t, 1H), 7.64 (dd, 1H), 7.92 (dd, 1H).

EXAMPLE 291-(2,3-dichlorophenyl)-N-[(1R)-1-phenylethyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (1R)-1-phenylethanamine instead of 2-methylbenzylamine.MS (ESI⁺) m/z 334 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.44 (d, 3H), 4.91(m, 1H), 7.22 (m, 1H), 7.28-7.37 (m, 4H), 7.57-7.64 (m, 2H), 7.96 (dd,1H).

EXAMPLE 301-(2,3-dichlorophenyl)-N-methyl-N-[(1R)-1-phenylethyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using N-methyl-N-[(1R)-1-phenylethyl]amine instead of2-methylbenzylamine. MS (ESI⁺) m/z 348 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.50 (d, 3H), 2.43 (s, 3H), 5.17 (m, 1H), 7.25-7.40 (m, 5H), 7.62 (t,1H), 7.93 (d, 2H).

EXAMPLE 311-(2,3-dichlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (1S)-2,3-dihydro-1H-inden-1-ylamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 346 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.92 (m, 1H), 2.5 (m, 1H), 2.7-3.0 (m, 2H), 5.34 (m, 1H), 7.15-7.30(m, 4H), 7.55 (t, 1H), 7.58 (t, 1H), 7.70 (dd, 1H), 7.91 (dd, 1H).

EXAMPLE 321-(2,3-dichlorophenyl)-N-[(1S)-1-phenylethyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (1S)-1-phenylethanamine instead of 2-methylbenzylamine.MS (ESI+) m/z 334 (M+H)⁺; ¹H NMR (300 MHz. DMSO-d₆) δ 1.45 (d, 3H), 4.91(m, 1H), 7.23 (m, 1H), 7.29-7.38 (m, 4H), 7.56-7.64 (m, 2H), 7.68 (dd,1H), 7.96 (dd, 1H).

EXAMPLE 331-(2,3-dichlorophenyl)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylmethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)methanamineinstead of 2-methylbenzylamine. MS (ESI⁺) m/z 361 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.04 (m, 2H), 2.85 (m, 4H), 4.44 (d, 2H), 7.53 (br s,1H), 7.61 (t, 1H), 7.68 (br t, 1H), 7.71 (dd, 1H), 7.96 (dd, 1H), 8.25(br s, 1H).

EXAMPLE 341-(2,3-dichlorophenyl)-N-(5,6,7,8-tetrahydroquinolin-3-ylmethyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-(5,6,7,8-tetrahydroquinolin-3-yl)methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 375 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.77 (m, 4H), 2.73 (m, 4H), 4.42 (d, 2H), 7.37 (br s, 1H), 7.61 (t,1H), 7.67 (br t, 1H), 7.71 (dd, 1H), 7.95 (dd, 1H), 8.25 (br d, 1H).

EXAMPLE 351-(2,3-dichlorophenyl)-N-(4-morpholin-4-ylbenzyl)-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using 1-(4-morpholin-4-ylphenyl)methanamine instead of2-methylbenzylamine. MS (ESI⁺) m/z 405 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 3.06 (m, 4H), 3.72 (m, 4H), 4.37 (d, 2H), 6.89 (d, 2H), 7.18 (d, 2H),7.55-7.62 (m, 2H), 7.68 (dd, 1H), 7.93 (dd, 1H).

EXAMPLE 36 1-(2-methylphenyl)-N-[(1R)-1-phenylethyl]-1H-tetrazol-5-amine

The title compound was prepared using the procedure described in Example1 except using (1R)-1-phenylethanamine instead of 2-methylbenzylamine.MS (ESI⁺) m/z 280 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.44 (d, 3H), 1.98(s, 3H), 4.88 (m, 1H), 7.22 (m, 1H), 7.26-7.58 (m, 9H).

EXAMPLE 371-(2,3-dichlorophenyl)-N-[(2-methylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

C-(2-methyl-pyridin-3-yl)-methylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 336 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.49 (s, 3H) 4.48 (d, J=5.42 Hz, 2H) 7.19 (dd,J=7.80, 4.75 Hz, 1H) 7.57-7.70 (m, 4H) 7.74 (dd, J=7.36, 1.36 Hz, 1H)7.95 (dd, J=8.14, 1.36 Hz, 1H) 8.33 (dd, J=4.75, 1.70 Hz, 1H).

EXAMPLE 381-(2,3-dichlorophenyl)-N-2,3-dihydro-1-benzofuran-3-yl-1H-tetrazol-5-amine

2,3-dihydro-benzofuran-3-ylamine (Turan-Zitouni, G.; Berge, G.;Noel-Artis, A. M.; Chevallet, P.; Fulcrand, P.; Castel, J.; Farmaco Ed.Sci. 43; 7-8; 1988; 643-656) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 349 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.33 (dd, J=9.83, 4.75 Hz, 1H) 4.76 (dd, J=9.83,8.48 Hz, 1H) 5.55-5.65 (m, 1H) 6.84 (d, J=8.14 Hz, 1H) 6.86-6.92 (m, 1H)7.18-7.26 (m, 1H) 7.37 (d, J=7.46 Hz, 1H) 7.56 (t, J=8.14 Hz, 1H) 7.68(dd, J=7.30, 1.70 Hz, 1H) 7.84 (d, J=7.80 Hz, 1H) 7.90 (dd, J=8.14, 1.70Hz, 1H).

EXAMPLE 39N-(1,1′-biphenyl-2-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

2-phenylbenzylamine was reacted with 2,3-dichlorophenylisothiocyanateaccording to the method of Example 78C to provide the title compound. MS(ESI⁺) m/z 397 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.42 (d, J=5.49Hz, 2H) 7.22-7.25 (m, 1H) 7.43-7.48 (m, 5H) 7.42-7.48 (m, 3H) 7.58-7.63(m, 2H) 7.65 (dd, J=3.00, 1.53 Hz, 1H) 7.93 (dd, J=7.93, 1.53 Hz, 1H).

EXAMPLE 40 1-(2,3-dichlorophenyl)-N-(2-ethoxybenzyl)-1H-tetrazol-5-amine

2-ethoxybenzylamine was reacted with 2,3-dichlorophenylisothiocyanateaccording to the method of Example 78C to provide the title compound. MS(ESI⁺) m/z 365 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31 (t, J=7.02Hz, 3H) 4.04 (q, J=6.86 Hz, 2H) 4.47 (d, J=5.62 Hz, 2H) 6.88 (t, J=7.49Hz, 1H) 6.96 (d, J=7.80 Hz, 1H) 7.19-7.24 (m, 2H) 7.45 (t, J=5.77 Hz,1H) 7.61 (t, J=8.11 Hz, 1H) 7.70 (dd, J=8.11, 1.56 Hz, 1H) 7.94 (dd,J=8.11, 1.56 Hz, 1H).

EXAMPLE 411-(2,3-dichlorophenyl)-N-(2-isopropoxybenzyl)-1H-tetrazol-5-amine

1-(2-isopropoxyphenyl)methanamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 379 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.26 (d, J=5.93 Hz, 6H) 4.45 (d, J=5.93 Hz, 2H)4.57-4.65 (m, 1H) 6.86 (t, J=7.49 Hz, 1H) 6.99 (d, J=8.42 Hz, 1H)7.18-7.23 (m, 2H) 7.40 (t, J=5.77 Hz, 1H) 7.61 (t, J=8.11 Hz, 1H) 7.70(dd, J=8.11, 1.56 Hz, 1H) 7.93 (dd, J=8.11, 1.56 Hz, 1H).

EXAMPLE 42N-(2-adamantylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

1-adamantanemethylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 379 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.43-1.49 (m, 6H) 1.54-1.69 (m, 6H) 1.89-1.96 (m,3H) 3.02 (d, J=4.68 Hz, 2H) 6.98 (t, J=6.40 Hz, 1H) 7.61 (t, J=8.11 Hz,1H) 7.65 (dd, J=3.00, 1.56 Hz, 1H) 7.93 (dd, J=7.80, 1.56 Hz, 1H).

EXAMPLE 431-(2-fluorophenyl)-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

2-(pyridin-2-yloxy)benzylamine hydrochloride was reacted with2-fluorophenylisothiocyanate according to the method of Example 78C toprovide the title compound. MS (ESI⁺) m/z 363 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 4.42 (d, J=6.10 Hz, 2H) 7.02 (d, J=8.24 Hz, 1H) 7.08 (d,J=8.24 Hz, 1H) 7.12 (dd, J=7.02, 4.88 Hz, 1H) 7.19-7.23 (m, 1H)7.29-7.34 (m, 1H) 7.38 (dd, J=7.63, 0.92 Hz, 1H) 7.43 (t, J=7.63 Hz, 1H)7.53-7.62 (m, 3H) 7.65-7.71 (m, 1H) 7.82-7.87 (m, 1H) 8.09 (dd, J=4.88,1.83 Hz, 1H).

EXAMPLE 441-(2-chlorophenyl)-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

2-(pyridin-2-yloxy)benzylamine hydrochloride was reacted with2-chlorophenylisothiocyanate according to the method of Example 78C toprovide the title compound. MS (ESI⁺) m/z 379 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 4.40 (d, J=5.80 Hz, 2H) 7.02 (d, J=8.24 Hz, 1H) 7.07 (d,J=7.93 Hz, 1H) 7.12 (dd, J=6.87, 5.34 Hz, 1H) 7.18-7.23 (m, 1H) 7.31 (s,1H) 7.40 (dd, J=7.63, 1.22 Hz, 1H) 7.48 (t, J=5.80 Hz, 1H) 7.55-7.60 (m,1H) 7.60-7.63 (m, 1H) 7.64-7.69 (m, 1H) 7.78 (dd, J=7.93, 1.22 Hz, 1H)7.83-7.88 (m, 1H) 8.09 (dd, J=5.03, 1.68 Hz, 1H).

EXAMPLE 451-(2,3-dichlorophenyl)-N-[(2-phenoxypyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 45A (2-phenoxypyridin-3-yl)methylamine

2-phenoxynicotinonitrile and Raney/nickel were processed according tothe Example 78B to afford the title compound. MS (ESI⁺) m/z 201 (M+H)⁺

EXAMPLE 45B1-(2,3-dichlorophenyl)-N-[(2-phenoxypyridin-3-yl)methyl]-1H-tetrazol-5-amine

The product from Example 45A was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 414 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.60 (d, J=5.49 Hz, 2H) 7.10-7.14 (m, 3H) 7.18-7.23(m, 1H) 7.38-7.44 (m, 2H) 7.62 (t, J=8.09 Hz, 1H) 7.72-7.79 (m, 3H) 7.95(dd, J=6.00, 1.53 Hz, 1H) 7.99-8.02 (m, 1H).

EXAMPLE 461-(2,3-dichlorophenyl)-N-[2-(2-methoxyphenoxy)benzyl]-1H-tetrazol-5-amine

2-(2-methoxyphenoxy)benzylamine hydrochloride was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 443 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 3.74 (s, 3H) 4.60 (d, J=5.93 Hz, 2H) 6.55 (dd,J=8.11, 0.94 Hz, 1H) 6.93-6.99 (m, 2H) 7.00-7.04 (m, 1H) 7.14-7.21 (m,3H) 7.34 (dd, J=7.49, 1.56 Hz, 1H) 7.57-7.61 (m, 1H) 7.62 (t, J=8.11 Hz,1H) 7.71 (dd, J=6.00, 1.25 Hz, 1H) 7.95 (dd, J=8.27, 1.40 Hz, 1H).

EXAMPLE 471-(2,3-dichlorophenyl)-N-3,4-dihydro-2H-chromen-4-yl-1H-tetrazol-5-amine

3,4-dihydro-2H-chromen-4-ylamine (Sebok, P.; Levai, A.; Timar, T.Heterocyclic Communications (1998), 4(6), 547-557) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 363 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.00-2.20 (m, 2H) 4.12-4.27 (m, 2H) 4.95-5.04 (m,1H) 6.77 (dd, J=8.14, 1.02 Hz, 1H) 6.83-6.90 (m, 1H) 7.12-7.19 (m, 1H)7.25 (dd, J=7.63, 1.19 Hz, 1H) 7.57 (t, J=7.97 Hz, 1H) 7.69 (d, J=9.00Hz, 1H) 7.70 (dd, J=7.97, 1.53 Hz, 1H) 7.90 (dd, J=8.14, 1.70 Hz, 1H).

EXAMPLE 481-(2,3-dichlorophenyl)-N-3,4-dihydro-2H-chromen-4-yl-1H-tetrazol-5-amineEXAMPLE 48A 2,3-dihydro-1-benzofuran-7-ylmethanol

2,3-Dihydrobenzofuran carboxylic acid (5.047 g) in tetrahydrofuran at−10° C. was treated dropwise with a solution of 1.0 Mborane.tetrahydrofuran (20 mL). The temperature was allowed to warm toroom temperature overnight, treated with additional 1.0 Mborane.tetrahydrofuran (10 mL), and stirred at room temperature for 2hours. The mixture was cooled to 5° C., slowly treated with methanol (20mL), and concentrated under reduced pressure. The residue was dissolvedin ethyl acetate, washed with saturated sodium bicarbonate (2×),saturated sodium chloride, dried (sodium sulfate), filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography (hexanes:ethyl acetate, 3:2) to providethe title compound. MS (DCI/NH₃) m/z 168 (M+NH₄)⁺; ¹H NMR (CDCl₃) δ 3.21(t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1H), 7.08 (dd, 1H), 7.14(dd, 1H).

EXAMPLE 48B 7-(bromomethyl)-2,3-dihydro-1-benzofuran

The product of Example 48A (4.06 g) and carbon tetrabromide (10.9 g)were combined in methylene chloride (100 mL) at 0° C. and treated withtriphenylphosphine (8.53 g) portionwise. The mixture was allowed to warmto room temperature, stirred overnight, concentrated under reducedpressure, and the residue was purified by flash chromatography (2% ethylacetate/hexanes) to provide the title compound. ¹H NMR (CDCl₃) δ 3.22(t, 2H), 4.50 (s, 2H), 4.65 (t, 2H), 6.81 (t, 1H), 7.12 (m, 2H).

EXAMPLE 48C 7-(azidomethyl)-2,3-dihydro-1-benzofuran

The product of Example 48B (4.40 g) in N,N-dimethylformamide (60 mL) atroom temperature was treated in one portion with sodium azide (5.37 g),stirred for 3 hours, poured into water and extracted with diethylether(2×100 mL). The organics were dried (sodium sulfate), filtered, and thefiltrate concentrated under reduced pressure. The residue was purifiedby flash chromatography (5% ethyl acetate/hexane) to provide the titlecompound. ¹H NMR (CDCl₃) δ 3.23 (t, 2H), 4.31 (s, 2H), 4.60 (t, 2H),6.85 (t, 1H), 7.06 (d, 1H), 7.19 (dd, 1H).

EXAMPLE 48D 1-(2,3-dihydro-1-benzofuran-7-yl)methanamine

The product of Example 48C (2.2 g) in tetrahydrofuran (10 mL) wastreated with lithium aluminumhydride (0.71 g) in tetrahydrofuran (20 mL)at 0° C. dropwise. The mixture was stirred at 0° C. for 90 minutes thencarefully treated in succession with water (0.7 mL), 15% sodiumhydroxide (0.7 mL) and water (2.1 mL). After stirring overnight, themixture was filtered through celite, the filter cake was washed withtetrahydrofuran (70 mL), and the filtrate concentrated under reducedpressure. The crude was dissolved in diethylether, washed with water,and extracted with 1N hydrochloric acid (2×20 mL). The acidic extractswere combined, basified with potassium carbonate, and extracted withmethylene chloride (4×). The organic extracts were combined, dried(potassium carbonate), filtered, and the filtrate was concentrated underreduced pressure to provide the title compound. MS (DCI/NH₃) m/z 150(M+H)⁺;

¹H NMR (CDCl₃) δ 3.21 (t, 2H), 3.82 (s, 2H), 4.59 (t, 2H), 6.81 (t, 1H),7.03 (d, 1H), 7.10 (dd, 1H).

EXAMPLE 48E1-(2,3-dichlorophenyl)-N-3,4-dihydro-2H-chromen-4-yl-1-tetrazol-5-amine

The product of Example 48D was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 363 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 3.17 (t, J=8.81 Hz, 2H) 4.40 (d, J=5.76 Hz, 2H) 4.53(t, J=8.65 Hz, 2H) 6.77 (t, J=7.46 Hz, 1H) 7.01-7.06 (m, 1H) 7.12 (dd,J=7.46, 1.02 Hz, 1H) 7.56-7.64 (m, 2H) 7.69 (dd, J=9.00, 1.70 Hz, 1H)7.94 (dd, J=7.97, 1.53 Hz, 1H).

EXAMPLE 491-(2,3-dichlorophenyl)-N-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-1H-tetrazol-5-amine

(5-methyl-3-phenyl-4-isoxazolyl)methylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 402 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.46 (s, 3H) 4.39 (d, J=4.75 Hz, 2H) 7.39-7.52 (m,5H) 7.55 (t, J=7.97 Hz, 1H) 7.63-7.68 (m, 2H) 7.91 (dd, J=7.80, 1.70 Hz,1H).

EXAMPLE 501-(2,3-dichlorophenyl)-N-[2-(2-methylphenoxy)benzyl]-1H-tetrazol-5-amine

2-(2-methylphenoxy)benzylamine hydrochloride was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 427 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.18 (s, 3H) 4.57 (d, J=5.76 Hz, 2H) 6.62 (dd,J=8.14, 1.02 Hz, 1H) 6.81 (dd, J=7.80, 1.02 Hz, 1H) 7.04-7.12 (m, 2H)7.16-7.26 (m, 2H) 7.29-7.34 (m, 1H) 7.39 (dd, J=7.63, 1.53 Hz, 1H)7.57-7.69 (m, 3H) 7.95 (dd, J=7.80, 1.70 Hz, 1H).

EXAMPLE 511-(2,3-dichlorophenyl)-N-[2-(pyrazin-2-yloxy)benzyl]-1H-tetrazol-5-amine

2-(pyrazin-2-yloxy)benzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 415 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.43 (d, J=5.76 Hz, 2H) 7.17 (dd, J=7.97, 1.19 Hz,1H) 7.22-7.29 (m, 1H) 7.31-7.39 (m, 1H) 7.44 (dd, J=7.46, 1.70 Hz, 1H)7.55-7.63 (m, 3H) 7.93 (dd, J=6.44, 3.39 Hz, 1H) 8.16 (dd, J=2.71, 1.36Hz, 1H) 8.36 (dd, J=2.71, 0.68 Hz, 1H) 8.51 (dd, J=1.02, 0.68 Hz, 1H).

EXAMPLE 52 1-(2,3-dichlorophenyl)-N-(3-nitrobenzyl)-1H-tetrazol-5-amine

3-nitrobenzylamine hydrochloride was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 366 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.61 (d, J=6.10 Hz, 2H) 7.60-7.68 (m, 2H) 7.74 (dd,J=9.00, 1.36 Hz, 1H) 7.80 (d, J=7.80 Hz, 1H) 7.88 (t, J=5.93 Hz, 1H)7.97 (dd, J=8.14, 1.36 Hz, 1H) 8.10-8.16 (m, 1H) 8.20 (t, J=1.70 Hz,1H).

EXAMPLE 531-(2,3-dichlorophenyl)-N-[(2-methoxypyridin-3-yl)methyl]-1H-tetrazol-5-amine

(2-methoxypyridin-3-yl)methylamine (WO2001060803) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 352 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 3.89 (s, 3H) 4.42 (d, J=5.76 Hz, 2H) 6.97 (dd,J=7.12, 5.09 Hz, 1H) 7.54-7.61 (m, 1H) 7.61-7.67 (m, 2H) 7.75 (dd,J=9.00, 1.70 Hz, 1H) 7.96 (dd, J=8.14, 1.36 Hz, 1H) 8.07 (dd, J=5.09,1.70 Hz, 1H).

EXAMPLE 541-(2,3-dichlorophenyl)-N-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 54A 1-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methanamine

2-(2,2,2-trifluoroethoxy)nicotinonitrile was processed according to themethod of Example 78B to provide the intermediate I. MS (ESI⁺) m/z 207(M+H)⁺.

EXAMPLE 54B1-(2,3-dichlorophenyl)-N-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The product of Example 54A was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 420 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.46 (d, J=5.76 Hz, 2H) 5.03 (q, J=8.93 Hz, 2H) 7.11(dd, J=7.46, 5.09 Hz, 1H) 7.59-7.70 (m, 3H) 7.75 (dd, J=8.14, 1.70 Hz,1H) 7.96 (dd, J=8.14, 1.70 Hz, 1H) 8.11 (dd, J=5.09, 2.03 Hz, 1H).

EXAMPLE 551-(2,3-dichlorophenyl)-N-[2-(4-methylpiperazin-1-yl)benzyl]-1H-tetrazol-5-amine

1-[2-(4-methylpiperazin-1-yl)phenyl]methanamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 385 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.22 (s, 3H) 2.37-2.48 (m, 4H) 2.83 (t, J=4.58 Hz,4H) 4.56 (d, J=5.76 Hz, 2H) 7.01-7.08 (m, 1H) 7.11 (dd, J=7.63, 1.02 Hz,1H) 7.19-7.24 (m, 1H) 7.24-7.30 (m, 1H) 7.55 (t, J=5.76 Hz, 1H) 7.60 (t,J=7.97 Hz, 1H) 7.68-7.73 (m, J=8.80, 1.36 Hz, 1H) 7.94 (dd, J=7.97, 1.53Hz, 1H).

EXAMPLE 56N-(5-chloro-2-methoxybenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

5-chloro-2-methoxybenzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 385 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 3.81 (s, 3H) 4.43 (d, J=5.76 Hz, 2H) 7.02 (d, J=8.82Hz, 1H) 7.22 (d, J=2.71 Hz, 1H) 7.29 (dd, J=8.48, 2.71 Hz, 1H) 7.58-7.67(m, 2H) 7.76 (dd, J=6.96, 1.70 Hz, 1H) 7.96 (dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 571-(2,3-dichlorophenyl)-N-[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]-1H-tetrazol-5-amine

(6-fluoro-4H-1,3-benzodioxin-8-yl)methylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 397 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.43 (d, J=5.76 Hz, 2H) 4.88 (s, 2H) 5.28 (s, 2H)6.84-6.96 (m, 2H) 7.61 (t, J=8.14 Hz, 1H) 7.63 (d, J=5.77 Hz, 1H) 7.77(dd, J=8.14, 1.36 Hz, 1H) 7.96 (dd, J=8.14, 1.70 Hz, 1H).

EXAMPLE 581-(2,3-dichlorophenyl)-N-(1-pyridin-3-ylethyl)-1H-tetrazol-5-amine

1-pyridin-3-yl-ethylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 336 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.48 (d, J=7.12 Hz, 3H) 4.90-5.01 (m, 1H) 7.31-7.39(m, 1H) 7.61 (t, J=10.50 Hz, 1H) 7.65 (d, J=7.80 Hz, 1H) 7.72 (dd,J=9.00, 1.70 Hz, 1H) 7.74-7.78 (m, 1H) 7.97 (dd, J=8.14, 1.70 Hz, 1H)8.45 (dd, J=4.75, 1.70 Hz, 1H) 8.59 (d, J=2.03 Hz, 1H).

EXAMPLE 594-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)-3-methoxybenzonitrile

4-(aminomethyl)-3-methoxybenzonitrile (WO9625426) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 376 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 3.88 (s, 3H) 4.49 (d, J=5.76 Hz, 2H) 7.34-7.43 (m,2H) 7.47 (d, J=1.36 Hz, 1H) 7.63 (t, J=8.14 Hz, 1H) 7.69 (t, J=5.93 Hz,1H) 7.76 (dd, J=9.00, 1.36 Hz, 1H) 7.96 (dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 601-(2,3-dichlorophenyl)-N-(quinolin-3-ylmethyl)-1H-tetrazol-5-amine

C-quinolin-3-yl-methylamine (Peel, Michael R.; Sternbach, Daniel D.Bioorg. Med. Chem. Lett. (1994), 4(23), 2753-8) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 372 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.68 (d, J=5.76 Hz, 2H) 7.52 (dd, J=8.31, 4.24 Hz,1H) 7.63 (t, J=8.14 Hz, 1H) 7.72 (dd, J=9.00, 1.70 Hz, 1H) 7.77 (dd,J=9.00, 1.70 Hz, 1H) 7.82-7.88 (m, 2H) 7.93-8.01 (m, 2H) 8.33 (dd,J=8.31, 1.19 Hz, 1H) 8.87 (dd, J=4.41, 1.70 Hz, 1H).

EXAMPLE 611-(2,3-dichlorophenyl)-N-(2-piperidin-1-ylbenzyl)-1H-tetrazol-5-amine

2-piperidinobenzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 404 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.47-1.66 (m, 6H) 2.74-2.81 (m, 4H) 4.56 (d, J=5.76Hz, 2H) 6.99-7.06 (m, 1H) 7.10 (dd, J=9.00, 1.02 Hz, 1H) 7.18-7.29 (m,2H) 7.55 (t, J=5.76 Hz, 1H) 7.61 (t, J=7.97 Hz, 1H) 7.71 (dd, J=6.50,1.70 Hz, 1H) 7.94 (dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 621-(2,3-dichlorophenyl)-N-({2-[(6-methylpyridin-3-yl)oxy]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 62A 2-[(6-methylpyridin-3-yl)oxy]nicotinonitrile

5-hydroxy-2-methylpyridine and 2-fluoronicotinonitrile were processedaccording to the method of Example 128B to provide the product. MS(ESI⁺) m/z 212 (M+H)⁺;

EXAMPLE 62B {2-[(6-methylpyridin-3-yl)oxy]pyridin-3-yl}methylamine

The product of Example 62A and Raney/nickel were processed according tothe method of Example 131C to provide the product. MS (ESI⁺) m/z 216(M+H)⁺.

EXAMPLE 62C1-(2,3-dichlorophenyl)-N-({2-[(6-methylpyridin-3-yl)oxy]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

The product of Example 62B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 429 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.48 (s, 3H) 4.61 (d, J=5.43 Hz, 2H) 7.13 (dd,J=7.29, 4.92 Hz, 1H) 7.31 (d, J=8.48 Hz, 1H) 7.50 (dd, J=8.31, 2.88 Hz,1H) 7.62 (t, J=8.14 Hz, 1H) 7.72-7.82 (m, 3H) 7.96 (dd, J=8.14, 1.70 Hz,1H) 7.99 (dd, J=4.92, 1.86 Hz, 1H) 8.28 (d, J=2.71 Hz, 1H).

EXAMPLE 63N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-2,3-dihydrofuro[2,3-b]pyridin-3-amineEXAMPLE 63A Furo[2,3-b]pyridin-3(2H)-one O-methyloxime

Furo[2,3-b]pyridin-3(2H)-one (Morita, Hiroyuki; Shiotani, Shunsaku; J.Heterocycl. Chem.; 23; 1986; 1465-1469). and the hydrochloride salt ofmethoxylamine were processed according to the method of Example 135A toprovide the product. MS (ESI⁺) m/z 165 (M+H)⁺.

EXAMPLE 63B 2,3-dihydrofuro[2,3-b]pyridin-3-amine

The product of Example 63A and Raney/nickel were processed according tothe method of Example 131C to provide the product. MS (ESI⁺) m/z 136(M+H)⁺.

EXAMPLE 63CN-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-2,3-dihydrofuro[2,3-b]pyridin-3-amine

The product of Example 63B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound.

MS (ESI⁺) m/z 350 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.37 (dd,J=9.83, 4.41 Hz, 1H) 4.81 (dd, J=9.83, 8.82 Hz, 1H) 5.58-5.67 (m, 1H)6.94 (dd, J=7.12, 5.09 Hz, 1H) 7.58 (t, J=7.97 Hz, 1H) 7.70 (dd, J=8.50,1.70 Hz, 1H) 7.75-7.80 (m, 1H) 7.86 (d, J=7.80 Hz, 1H) 7.92 (dd, J=8.14,1.70 Hz, 1H) 8.06 (dd, J=4.92, 1.53 Hz, 1H).

EXAMPLE 641-(2,3-dichlorophenyl)-N-(2,4-difluorobenzyl)-1H-tetrazol-5-amine

2,4-difluorobenzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 356 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.49 (d, J=5.76 Hz, 2H) 7.02-7.11 (m, 1H) 7.18-7.27(m, 1H) 7.39-7.50 (m, 1H) 7.61 (t, J=8.14 Hz, 1H) 7.69-7.75 (m, 2H) 7.95(dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 65N-(2-chloro-4-fluorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

2-chloro-4-fluorobenzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 373 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.53 (d, J=5.76 Hz, 2H) 7.18-7.26 (m, 1H) 7.41-7.48(m, 2H) 7.62 (t, J=8.14 Hz, 1H) 7.71-7.78 (m, 2H) 7.96 (dd, J=8.14, 1.36Hz, 1H)

EXAMPLE 66N-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)phenyl]-N-methylacetamide

N-[3-(aminomethylphenyl]-N-methylacetamide hydrochloride was reactedwith 2,3-dichlorophenylisothiocyanate according to the method of Example78C to provide the title compound. MS (ESI⁺) m/z 392 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.74 (s, 3H) 3.13 (s, 3H) 4.51 (d, J=5.76 Hz, 2H)7.18-7.32 (m, 3H) 7.40 (t, J=7.80 Hz, 1H) 7.62 (t, J=7.97 Hz, 1H)7.69-7.76 (m, 2H) 7.95 (dd, J=8.14, 1.70 Hz, 1H).

EXAMPLE 671-(2,3-dichlorophenyl)-N-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-tetrazol-5-amine

4-fluoro-2-trifluoromethylbenzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 407 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.64 (d, J=5.42 Hz, 2H) 7.50-7.59 (m, 1H) 7.59-7.67(m, 3H) 7.76 (dd, J=7.97, 1.53 Hz, 1H) 7.82 (t, J=5.76 Hz, 1H) 7.97 (dd,J=8.14, 1.36 Hz, 1H).

EXAMPLE 681-(2,3-dichlorophenyl)-N-(5-fluoro-2-methylbenzyl)-1H-tetrazol-5-amine

5-fluoro-2-methylbenzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 352 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.45 (d, J=5.76 Hz, 2H) 6.94-7.02 (m, 1H) 7.05 (dd,J=10.17, 2.71 Hz, 1H) 7.20 (dd, J=8.14, 6.10 Hz, 1H) 7.59-7.67 (m, 2H)7.75 (dd, J=8.50, 1.70 Hz, 1H) 7.95 (dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 691-(2,3-dichlorophenyl)-N-(2,4,5-trifluorobenzyl)-1H-tetrazol-5-amine

2,4,5-trifluorobenzylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 375 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.48 (d, J=5.76 Hz, 2H) 7.39-7.48 (m, 1H) 7.49-7.58(m, 1H) 7.63 (t, J=8.14 Hz, 1H) 7.71-7.78 (m, 2H) 7.96 (dd, J=8.14, 1.70Hz, 1H).

EXAMPLE 701-(2,3-dichlorophenyl)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-1H-tetrazol-5-amine

5-fluoro-2,3-dihydro-1H-Inden-1-amine (EP538134) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 365 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.86-2.02 (m, 1H) 2.52-2.59 (m, 1H) 2.75-3.01 (m,2H) 5.24-5.36 (m, 1H) 6.95-7.04 (m, 1H) 7.08 (dd, J=9.15, 2.37 Hz, 1H)7.27 (dd, J=8.31, 5.26 Hz, 1H) 7.52 (d, J=8.48 Hz, 1H) 7.58 (t, J=7.97Hz, 1H) 7.70 (dd, J=8.50, 1.36 Hz, 1H) 7.91 (dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 711-(2,3-difluorophenyl)-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

2-(pyridin-2-yloxy)benzylamine hydrochloride was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 381 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.43 (d, J=6.10 Hz, 2H) 6.98-7.03 (m, 1H) 7.06-7.11(m, 1H) 7.11-7.14 (m, 1H) 7.22 (dt, J=7.54, 1.19 Hz, 1H) 7.29-7.36 (m,1H) 7.39 (dd, J=7.46, 1.70 Hz, 1H) 7.42-7.48 (m, 2H) 7.65-7.79 (m, 2H)7.81-7.88 (m, 1H) 8.08-8.12 (m, 1H).

EXAMPLE 72N-({6-chloro-5-fluoro-2-[(1-methylpyrrolidin-3-yl)oxy]pyridin-3-yl}methyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 72A6-chloro-5-fluoro-2-[(1-methylpyrrolidin-3-yl)oxy]nicotinonitrile

3-cyano-2,6-dichloro-5-fluoropyridine was reacted with1-methyl-pyrrolidin-3-ol according to the method of Example 85A toprovide the title compound. MS (ESI⁺) m/z 256 (M+H)⁺.

EXAMPLE 72B{6-chloro-5-fluoro-2-[(1-methylpyrrolidin-3-yl)oxy]pyridin-3-yl}methylamine

The product from Example 72A according to the method of Example 78Bprovided the title compound. MS (ESI⁺) m/z 260 (M+H)⁺.

EXAMPLE 72CN-({6-chloro-5-fluoro-2-[(1-methylpyrrolidin-3-yl)oxy]pyridin-3-yl}methyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The product of Example 72B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 473 (M+H)⁺. ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.76-1.88 (m, 1H) 2.25 (s, 3H) 2.26-2.36 (m, 2H)2.63-2.78 (m, 3H) 4.45 (d, J=5.42 Hz, 2H) 5.29-5.38 (m, 1H) 7.63 (t,J=7.97 Hz, 1H) 7.68-7.75 (m, 2H) 7.78 (dd, J=6.50, 1.36 Hz, 1H) 7.96(dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 731-(2,3-dichlorophenyl)-N-{[4-(4-fluorophenyl)-1,3-thiazol-5-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 73A5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(4-fluorophenyl)-1,3-thiazole

4-fluoro-phenyl-boronic acid and the product from Example 113C weretreated according to the method of Example 113D to provide the titlecompound. MS (DCI/NH₃) m/z 324 (M+H)⁺.

EXAMPLE 73B [4-(4-fluorophenyl)-1,3-thiazol-5-yl]methanol

The product from Example 73A following the same procedure as Example 76Dgave the title compound. MS (DCI/NH₃) m/z 210 (M+H)⁺.

EXAMPLE 73C 5-(azidomethyl)-4-(4-fluorophenyl)-1,3-thiazole

The product from Example 73B following the same procedure as Example 77Agave the title compound. MS (DCI/NH₃) m/z 235 (M+H)⁺.

EXAMPLE 73D [4-(4-fluorophenyl)-1,3-thiazol-5-yl]methylamine

The product from Example 73C following the same procedure as Example 77Bgave the title compound. MS (DCI/NH₃) m/z 209 (M+H)⁺

EXAMPLE 73E1-(2,3-dichlorophenyl)-N-{[4-(4-fluorophenyl)-1,3-thiazol-5-yl]methyl}-1H-tetrazol-5-amine

The product from Example 73D was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 422 (M+H)⁺. ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.79 (d, J=5.43 Hz, 2H) 7.27-7.36 (m, 2H) 7.61 (t,J=7.97 Hz, 1H) 7.68 (dd, J=6.00, 1.70 Hz, 1H) 7.71-7.79 (m, 2H) 7.95(dd, J=6.10, 3.00 Hz, 1H) 7.96-8.02 (m, 1H) 9.04 (s, 1H).

EXAMPLE 741-(2,3-dichlorophenyl)-N-[(4-thien-3-yl-1,3-thiazol-5-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 74A5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-thien-3-yl-1,3-thiazole

3-thiopheneboronic acid and the product from Example 113C were treatedaccording to the method of Example 113D to provide the title compound.MS (DCI/NH₃) m/z 312 (M+H)⁺.

EXAMPLE 74B (4-thien-3-yl-1,3-thiazol-5-yl)methanol

The product from Example 74A following the same procedure as Example 76Dgave the title compound. MS (DCI/NH₃) m/z 198 (M+H)⁺.

EXAMPLE 74C 5-(azidomethyl)-4-thien-3-yl-1,3-thiazole

The product from Example 74B following the same procedure as Example 77Agave the title compound. MS (DCI/NH₃) m/z 223 (M+H)⁺.

EXAMPLE 74D (4-thien-3-yl-1,3-thiazol-5-yl)methylamine

The product from Example 74C following the same procedure as Example 77Bgave the title compound. MS (DCI/NH₃) m/z 197 (M+H)⁺

EXAMPLE 74E1-(2,3-dichlorophenyl)-N-[(4-thien-3-yl-1,3-thiazol-5-yl)methyl]-1H-tetrazol-5-amine

The product from Example 74D was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 410 (M+H)⁺. ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.84 (d, J=5.76 Hz, 2H) 7.53 (dd, J=5.09, 1.36 Hz,1H) 7.61 (t, J=8.14 Hz, 1H) 7.67 (dd, J=6.00, 1.36 Hz, 1H) 7.69 (dd,J=9.00, 1.70 Hz, 1H) 7.85 (dd, J=3.05, 1.36 Hz, 1H) 7.95 (dd, J=8.14,1.70 Hz, 1H) 8.00 (t, J=5.59 Hz, 1H) 8.99 (s, 1H).

EXAMPLE 751-(2,3-dichlorophenyl)-N-(pyridin-2-ylmethyl)-1H-tetrazol-5-amineEXAMPLE 75A 2,3-dichlorophenylisocyanide dichloride

The title compound was prepared according to the procedure as describedin Kuehle, Engelbert; Anders, Bertram; Zumach, Gerhard, AngewandteChemie (1967), 79(15), 663-80.

EXAMPLE 75B 5-chloro-1-(2,3-dichlorophenyl)-1H-tetrazole

A solution of sodium azide (2.47 g, 17.24 mmol) andtetra-n-butylammonium bromide (548 mg, 1.7 mmol) in 8 ml of water wasadded to a solution of the product of Example 75A (5.95 g, 25.5 mmol) in40 ml of toluene. The reaction was stirred at room temperature for 3 h.The organic layer was separated off and the aqueous layer was extractedwith toluene. The combined organic extracts were dried, filtered andconcentrated. The product was purified by flash chromatography on SiO₂with Hex:EtOAc (1:1) to provide the title compound. MS (ESI⁺) m/z 250(M+H)⁺.

EXAMPLE 75C1-(2,3-dichlorophenyl)-N-(pyridin-2-ylmethyl)-1H-tetrazol-5-amine

A mixture of the product from Example 75B (150 mg, 0.604 mmol),2-(aminomethyl)pyridine (98 mg, 0.903 mmol) and triethylamine (252 μL,1.807 mmol) in 5 ml of THF was heated at reflux for 8 h. The solvent wasevaporated under reduced pressure at the product purified by preparativeHPLC on a waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size)using a gradient of 10% to 100% acetonitrile:ammonium acetate (10 mM)over 15 min at a flow rate of 70 mL/min to provide the title compound.MS (ESI⁺) m/z 322 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.56 (d,J=5.76 Hz, 2H) 7.24-7.30 (m, 1H) 7.31-7.36 (m, 1H) 7.63 (t, J=7.97 Hz,1H) 7.75 (dd, J=7.80, 1.70 Hz, 2H) 7.77-7.83 (m, 1H) 7.96 (dd, J=8.14,1.70 Hz, 1H) 8.48-8.52 (m, 1H).

EXAMPLE 763-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-phenolEXAMPLE 76A 3-(tert-butyl dimethyl-silanyloxy)-benzonitrile

A mixture of 3-hydroxy-benzonitrile (5.0 g, 42.0 mmol) and imidazole(7.15 g, 105 mmol) in N,N-dimethylformamide (100 mL) was treated withtert-butyl-chloro-dimethyl-silane (7.6 g, 50.4 mmol) inN,N-dimethylformamide (50 mL) over 10 min. The reaction was stirred atrt overnight. The reaction mixture was poured into water, and extractedwith ethyl acetate (2×). The solvent was removed, and the resultingresidue was chromatographered using hexane/ethyl acetate (10:1) to givethe title compound (9.27 g, 95%). MS (DCI/NH₃) m/z 234 (M+1)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.26 (s, 6H) 1.00 (s, 9H) 7.26 (dq, J=7.93,1.22 Hz, 1H) 7.35 (t, J=2.44 Hz, 1H) 7.50 (m, 2H).

EXAMPLE 76B1-[3-(tert-Butyl-dimethyl-silanyloxy)-benzyl]-3-(2,3-dichloro-phenyl)-thiourea

Part A

To a solution of the product from Example 76A (200 mg, 0.86 mmol) indiethyl ether (20 mL) was added lithium aluminium hydride (1 M intetrahydrofuran) (1.72 mL, 1.72 mmol) dropwise at rt. The reactionmixture was refluxed for 2 hr. Quenched with water, the mixture wasextracted with ethyl acetate (2×). The organic layers were combined,washed with water, and concentrated to afford a residue (181 mg, 0.76mmol).

Part B

A solution of the product from part A of Example 76B in tetrahydrofuran(10 mL) was treated with 2,3-dichlorophenyl isothiocyanate (155 mg, 0.76mmol). The reaction was stirred for 1 hr at rt. The solution wasconcentrated to dryness and the residue was chromatographered usingdichloromethane/hexane (1:1) then dichloromethane to give the titlecompound (173 mg, 52%). MS (DCI/NH₃) m/z 441 (M)⁺, 442 (M+2)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.18 (s, 6H) 0.95 (s, 9H) 4.69 (s, 2H) 6.73(dd, J=7.36, 1.84 Hz, 1H) 6.84 (brs, 1H) 6.91 (d, J=7.36 Hz, 1H) 7.21(t, J=7.67 Hz, 1H) 7.35 (t, J=7.98 Hz, 1H) 7.51 (dd, J=8.29, 1.53 Hz,1H) 7.59 (d, J=7.36 Hz, 1H) 8.41 (s, 1H) 9.41 (s, 1H).

EXAMPLE 76C[3-(tert-Butyl-dimethyl-silanyloxy)-benzyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine

A mixture of the product from Part B of Example 76B (170 mg, 0.4 mmol),mercury acetate (127 mg, 0.4 mmol) and sodium azide (85 mg, 1.32 mmol)in tetrahydrofuran (8 mL) was stirred overnight at rt. The solution wasconcentrated to dryness and the residue was chromatographered usingdichloromethane to give the title compound (137 mg, 76%). MS (DCI/NH₃)m/z 450 (M)⁺, 452 (M+2)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.15 (s, 6H)0.93 (s, 9H) 4.43 (d, J=5.93 Hz, 2H) 6.71 (dd, J=8.11, 2.50 Hz, 1H) 6.82(t, J=1.87 Hz, 1H) 6.91 (d, J=8.11 Hz, 1H) 7.19 (t, J=7.80 Hz, 1H) 7.61(t, J=8.11 Hz, 1H) 7.66 (t, J=6.24 Hz, 1H) 7.67 (dd, J=7.80, 1.56 Hz,1H) 7.94 (dd, J=8.11, 1.56 Hz, 1H).

EXAMPLE 76D3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-phenol

The product from Example 76C (240 mg, 0.53 mmol) in tetrahydrofuran (10mL) was treated with tetrabutylammonium fluoride (1 M intetrahydrofuran) (800 μL, 0.8 mmol). The reaction mixture was stirredfor 1 hr at rt. The solution was concentrated to dryness and the residuewas partitioned between ethyl acetate and water. The organic layer wasdried and the resulting residue was chromatographered using hexane/ethylacetate (1:1) to give the title compound (140 mg, 79%). MS (DCI/NH₃) m/z336 (M)⁺, 338 (M+2)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.39 (d, J=5.93Hz, 2H) 6.63 (dd, J=8.11, 1.56 Hz, 1H) 6.73 (m, 2H) 7.10 (t, J=7.80 Hz,1H) 7.61 (m, 3H) 7.68 (dd, J=8.11, 1.56 Hz, 1H) 7.94 (dd, J=8.11, 1.25Hz, 1H) 9.27 (brs, 1H). Anal. Calcd for C₁₄H₁₁N₅Cl₂₀: C, 50.02; H, 3.30;N, 20.83. Found: C, 50.37; H, 3.44; N, 19.56.

EXAMPLE 77[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(pyrimidin-2-yloxy)-benzyl]-amineEXAMPLE 77A 2-(3-Azidomethyl-phenoxy)-pyrimidine

To a mixture of 3-(pyrimidin-2-yloxy)-phenyl-methanol (500 mg, 2.47mmol) and triethylamine (625 μL, 4.5 mmol) in dichloromethane (40 mL)was added MsCl (2.33 uL, 3.0 mmol) at 0° C. The reaction was kept at 0°C. for 15 min. Removal of the solvent, the residue was dissolved inN,N-dimethylformamide (30 mL) and then treated with sodium azide (803mg, 12.4 mmol). The reaction mixture was heated at 80° C. for 4 hr. Thereaction mixture was poured into water, and extracted with ethyl acetate(2×). The solvent was removed, and the resulting residue waschromatographered using hexane/ethyl acetate (2:1) to give the titlecompound (483 mg, 86%). MS (DCI/NH₃) m/z 228 (M+1)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 4.49 (s, 2H) 7.19 (dd, J=8.11, 2.18 Hz, 1H) 7.21 (t,J=1.87 Hz, 1H) 7.26 (d, J=7.18 Hz, 1H) 7.27 (t, J=4.68 Hz, 1H) 7.47 (t,J=7.80 Hz, 1H) 8.64 (s, 1H) 8.65 (s, 1H).

EXAMPLE 77B 3-(Pyrimidin-2-yloxy)-benzylamine

The product from Example 77A (480 mg, 2.13 mmol) in ethanol (40 mL) wastreated with Pd/C (75 mg) at rt. The reaction mixture was stirred for 3hr at rt under the hydrogen balloon. Removal of the solvent gave thetitle compound (428 mg, 100%). MS (DCI/NH₃) m/z 202 (M+1)⁺. ¹H NMR (500MHz, DMSO-d₆) δ ppm 3.74 (s, 2H) 7.01 (dd, J=7.93, 1.83 Hz, 1H) 7.16 (s,1H) 7.21 (d, J=7.93 Hz, 1H) 7.25 (t, J=4.88 Hz, 1H) 7.35 (t, J=7.63 Hz,1H) 8.63 (s, 1H) 8.65 (s, 1H).

EXAMPLE 77C1-(2,3-Dichloro-phenyl)-3-[3-(pyrimidin-2-yloxy)-benzyl]-thiourea

The title compound was prepared using the procedure as described in PartB of Example 76B, substituting the product of Example 77B for theproduct from Part A of Example 76B. MS (DCI/NH₃) m/z 403 (M)⁺, 405(M+2)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.77 (s, 2H) 7.09 (dd, J=8.24,1.83 Hz, 1H) 7.15 (s, 1H) 7.22 (d, J=7.63 Hz, 1H) 7.27 (t, J=4.58 Hz,1H) 7.34 (t, J=8.24 Hz, 1H) 7.41 (t, J=7.93 Hz, 1H) 7.51 (dd, J=7.93,1.22 Hz, 1H) 7.60 (d, J=7.02 Hz, 1H) 8.46 (brs, 1H) 8.64 (s, 1H) 8.65(s, 1H) 9.45 (s, 1H).

EXAMPLE 77D[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(pyrimidin-2-yloxy)-benzyl]-amine

The title compound was prepared using the procedure as described inExample 76C, substituting the product of Example 77C for the productfrom part B of Example 76B. MS (DCI/NH₃) m/z 414 (M), 416 (M+2). ¹H (400MHz, DMSO-d₆) δ ppm 4.51 (d, J=5.83 Hz, 2H) 7.07 (dd, J=7.36, 1.84 Hz,1H) 7.12 (t, J=2.15 Hz, 1H) 7.20 (d, J=7.67 Hz, 1H) 7.25 (t, J=4.91 Hz,1H) 7.38 (t, J=7.67 Hz, 1H) 7.59 (t, J=7.98 Hz, 1H) 7.70 (dd, J=7.98,1.53 Hz, 1H) 7.71 (t, J=6.44 Hz, 1H) 7.93 (dd, J=8.29, 1.53 Hz, 1H) 8.61(s, 1H) 8.62 (s, 1H).

EXAMPLE 78[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(5-methyl-pyridin-2-yloxy)-benzyl]-amineEXAMPLE 78A 3-(5-Methyl-pyridin-2-yloxy)-benzonitrile

A mixture of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol),2-fluoro-5-methyl pyridine (467 mg, 4.17 mmol) and K₂CO₃ (150 mg) inN,N-dimethylformamide (5 mL) was heated at 150° C. overnight. Thereaction mixture was poured into water, and extracted with ethyl acetate(2×). The solvent was removed, and the resulting residue waschromatographered using hexane/ethyl acetate (2:1) to give the titlecompound (315 mg, 36%). MS (DCI/NH₃) m/z 211 (M+1)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.25 (s, 3H) 7.02 (d, J=8.59 Hz, 1H) 7.45 (ddd, J=8.29,1.53, 0.92 Hz, 1H) 7.61 (m, 3H) 7.71 (ddd, J=8.29, 2.46, 0.61 Hz, 1H)7.99 (dt, J=2.45, 0.61 Hz, 1H).

EXAMPLE 78B 3-(5-Methyl-pyridin-2-yloxy)-benzylamine

The product of Example 78A (315 mg, 1.49 mmol) in 20% NH₃-methanol (30mL) was treated with Raney Nickel (3.15 g). The mixture was hydrogenatedunder the pressure of 60 psi in a shaker for 19 hr. The solution wasfiltered through a nylon membrane and the filtrate was concentrated toafford the title compound (315 mg, 98%). MS (DCI/NH₃) m/z 215 (M+1)⁺.

EXAMPLE 78C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(5-methyl-pyridin-2-yloxy)-benzyl]-amine

The product from Example 78B (315 mg, 1.49 mmol) in tetrahydrofuran (40mL) was treated with 2,3-dichlorophenyl isothiocyanate (213 μL, 1.49mmol). The reaction mixture was stirred for 1 hr at rt. To the solutionwas added mercury acetate (473 mg, 1.49 mmol) and sodium azide (316 mg,4.93 mmol), and the mixture was stirred overnight at rt. Filtered theprecipitate, ant the filtrate was concentrated to dryness and theresidue was purified by C18 HPLC (20%-95%-ammonium acetate) to give thetitle compound (80.9 mg, 13%). MS (DCI/NH₃) m/z 427 (M)⁺, 429 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.24 (s, 3H) 4.47 (d, J=6.14 Hz, 2H) 6.90(d, J=8.29 Hz, 1H) 6.95 (dd, J=7.98, 1.23 Hz, 1H) 7.00 (t, J=1.53 Hz,1H) 7.12 (d, J=7.36 Hz, 1H) 7.33 (t, J=7.67 Hz, 1H) 7.59 (t, J=7.98 Hz,1H) 7.67 (m, 3H) 7.92 (dd, J=7.98, 1.53 Hz, 1H) 7.96 (d, J=2.45 Hz, 1H).

EXAMPLE 79[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(1-methyl-piperidin-4-yloxy)-benzyl]-amineEXAMPLE 79A 3-(1-Methyl-piperidin-4-yloxy)-benzonitrile

To a solution of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol),1-methyl-piperidin-4-ol (467 mg, 4.17 mmol) and triphenyl phosphine(1.64 g, 6.26 mmol) in tetrahydrofuran (40 mL) was added diisopropylazodicarboxylate (1.23 μL, 6.26 mmol) dropwise. The reaction mixture wasstirred for 4 hr at rt. The solution was concentrated to dryness and theresidue was chromatographered using ethyl acetate then ethylacetate/methanol (8:1) to give the title compound (380 mg, 42%). MS(DCI/NH₃) m/z 217 (M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (m, 2H)1.91 (m, 2H) 2.15 (m, 2H) 2.16 (s, 3H) 2.60 (m, 2H) 4.46 (m, 1H) 7.28(dd, J=7.67, 1.84 Hz, 1H) 7.35 (d, J=7.36 Hz, 1H) 7.45 (m, 2H).

EXAMPLE 79B 3-(1-Methyl-piperidin-4-yloxy)-benzylamine

The title compound was prepared using the procedure as described inExample 78B, substituting the product of Example 79A for the product ofExample 78A. MS (DCI/NH₃) m/z 221 (M+1)⁺.

EXAMPLE 79C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(1-methyl-piperidin-4-yloxy)-benzyl]-amine

The product of Example 79B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound MS (DCI/NH₃) m/z 433 (M)⁺, 435 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.60 (m, 2H) 1.88 (m, 2H) 2.14 (m, 2H) 2.16(s, 3H) 2.59 (m, 2H) 4.29 (m, 1H) 4.44 (d, J=5.93 Hz, 2H) 6.81 (dd,J=8.11, 2.50 Hz, 1H) 6.86 (d, J=8.11 Hz, 1H) 6.89 (d, J=1.87 Hz, 1H)7.20 (t, J=8.11 Hz, 1H) 7.61 (t, J=8.11 Hz, 1H) 7.65 (t, J=5.93 Hz, 1H)7.94 (dd, J=8.11, 1.56 Hz, 1H).

EXAMPLE 80[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(5-nitro-pyridin-2-yloxy)-benzyl]-amineEXAMPLE 80A [3-(5-Nitro-pyridin-2-yloxy)-benzyl]-carbamic acidtert-butyl ester

A mixture of (3-hydroxy-benzyl)-carbamic acid tert-butyl ester (250 mg,1.12 mmol), 2-fluoro-5-nitro-pyridine (150 mg, 1.12 mmol) and K₂CO₃ (120mg) in N,N-dimethylformamide (3 mL) was heated under microwave conditionat 100° C. for 10 min. The reaction mixture was poured into water, andextracted with ethyl acetate (2×). The solvent was removed, and theresulting residue was chromatographered using hexane/ethyl acetate (7:1)to give the title compound (165 mg, 43%). MS (DCI/NH₃) m/z 346 (M+1)⁺.

EXAMPLE 80B[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(5-nitro-pyridin-2-yloxy)-benzyl]-amine

The product of Example 80A (165 mg, 0.478 mmol) was treated withtrifluoroacetic acid (2 mL) for 5 min at rt. Removal of trifluoroaceticacid, the residue was dissolved in tetrahydrofuran (15 mL) and basifiedwith triethylamine (167 μL, 1.2 mmol). To the mixture was added2,3-dichlorophenyl isothiocyanate (68 μL, 0.478 mmol). The reactionmixture was stirred for 1 hr at rt. To the solution was added mercurychloride (130 mg, 0.478 mmol), sodium azide (101 mg, 1.58 mmol) andtriethylamine (134 μL, 0.96 mmol), and the mixture was stirred overnightat rt. Filtered the precipitate, and the filtrate was concentrated todryness and the residue was purified by C18 HPLC (20%-95%-ammoniumacetate) purification to give the title compound (87.8 mg, 40%). MS(DCI/NH₃) m/z 458 (M)⁺, 460 (M+2)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.53(d, J=5.93 Hz, 2H) 7.12 (ddd, J=8.11, 2.50, 0.94 Hz, 1H) 7.16 (t, J=1.87Hz, 1H) 7.25 (d, J=9.67 Hz, 1H) 7.26 (d, J=7.80 Hz, 1H) 7.43 (t, J=7.80Hz, 1H) 7.60 (t, J=8.11 Hz, 1H) 7.71 (dd, J=7.80, 1.56 Hz, 1H) 7.73 (t,J=5.93 Hz, 1H) 7.94 (dd, J=8.11, 1.56 Hz, 1H) 8.62 (dd, J=9.05, 2.81 Hz,1H) 9.01 (dd, J=2.81, 0.62 Hz, 1H)

EXAMPLE 81[3-(5-Chloro-pyridin-2-yloxy)-benzyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amineEXAMPLE 81A 3-(5-Chloro-pyridin-2-yloxy)-benzonitrile

3-Hydroxy-benzonitrile was reacted with 2,5-dichloro-pyridine accordingto the method of Example 78A to provide the title compound. MS (DCI/NH₃)m/z 231 (M)⁺, 233 (M+2)⁺.

EXAMPLE 81B 3-(5-Chloro-pyridin-2-yloxy)-benzylamine

The title compound was prepared according to the method of Example 78B,substituting the product of Example 81A for the product of Example 78A.MS (DCI/NH₃) m/z 235 (M)⁺, 237 (M+2)⁺.

EXAMPLE 81C[3-(5-Chloro-pyridin-2-yloxy)-benzyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine

The product from Example 81B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 447 (M)⁺, 449 (M+2)⁺. ¹HNMR ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.50 (d, J=6.24 Hz, 2H) 7.03 (dd,J=8.73, 2.50 Hz, 1H) 7.07 (t, J=1.56 Hz, 1H) 7.08 (dd, J=8.73, 0.62 Hz,1H) 7.18 (d, J=7.49 Hz, 1H) 7.37 (t, J=8.11 Hz, 1H) 7.60 (t, J=7.80 Hz,1H) 7.70 (m, 2H) 7.94 (dd, J=8.11, 1.25 Hz, 1H) 7.95 (dd, J=8.73, 2.81Hz, 1H) 8.18 (d, J=3.12 Hz, 1H).

EXAMPLE 82[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(3-methyl-pyridin-2-yloxy)-benzyl]-amineEXAMPLE 82A 3-(3-Methyl-pyridin-2-yloxy)-benzonitrile

3-Hydroxy-benzonitrile was reacted with 2-fluoro-3-methylpyridineaccording to the method of Example 78A to provide the title compound. MS(DCI/NH₃) m/z 211 (M+1)⁺.

EXAMPLE 82B 1-{3-[(3-methylpyridin-2-yl)oxy]phenyl}methanamine

The title compound was prepared using the method of Example 78B,substituting the product of Example 82A for the product of Example 78A.MS (DCI/NH₃) m/z 215 (M+1)⁺.

EXAMPLE 82C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(3-methyl-pyridin-2-yloxy)-benzyl]-amine

The product from Example 82B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 427 (M)⁺, 429 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.28 (s, 3H) 4.49 (d, J=6.24 Hz, 2H) 6.97(dd, J=7.80, 2.18 Hz, 1H) 7.02 (t, J=1.87 Hz, 1H) 7.05 (dd, J=7.18, 4.68Hz, 1H) 7.13 (d, J=7.49 Hz, 1H) 7.34 (t, J=7.80 Hz, 1H) 7.60 (t, J=7.80Hz, 1H) 7.67 (d, J=1.56 Hz, 1H) 7.69 (d, J=1.56 Hz, 1H) 7.71 (dq,J=7.18, 0.94 Hz, 1H) 7.92 (m, 1H) 7.93 (dd, J=8.11, 1.56 Hz, 1H)

EXAMPLE 83[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(4-methyl-pyridin-2-yloxy)-benzyl]-amineEXAMPLE 83A 3-(4-Methyl-pyridin-2-yloxy)-benzonitrile

3-Hydroxy-benzonitrile was reacted with 2-fluoro-4-methylpyridineaccording to the method of Example 78A to provide the title compound. MS(DCI/NH₃) m/z 211 (M+1)⁺.

EXAMPLE 83B 3-(4-Methyl-pyridin-2-yloxy)-benzylamine

The title compound was prepared using the method of Example 78B,substituting the product of Example 83A for the product of Example 78A.MS (DCI/NH₃) m/z 215 (M+1)⁺.

EXAMPLE 83C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[3-(4-methyl-pyridin-2-yloxy)-benzyl]-amine

The product from Example 83B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 427 (M)⁺, 429 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H) 4.49 (d, J=5.93 Hz, 2H) 6.82(m, 1H) 6.97 (m, 2H) 7.03 (t, J=1.87 Hz, 1H) 7.15 (d, J=7.49 Hz, 1H)7.35 (t, J=8.11 Hz, 1H) 7.60 (t, J=8.11 Hz, 1H) 7.68 (dd, J=7.80, 1.25Hz, 1H) 7.70 (t, J=6.24 Hz, 1H) 7.93 (dd, J=8.11, 1.56 Hz, 1H) 7.99 (d,J=4.99 Hz, 1H).

EXAMPLE 84[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-4-yloxy)-benzyl]-amineEXAMPLE 84A 2-(1-Methyl-piperidin-4-yloxy)-benzonitrile

To a mixture of 2-fluoro-benzonitrile (1.6 g, 13.2 mmol) and1-methyl-piperidin-4-ol (1.52 g, 13.2 mmol) in dioxane (50 mL) was addedNaH (60%) (634 mg, 15.8 mmol) in portion. The reaction was heated at 50°C. overnight. The mixture was poured into water, and extracted withethyl acetate (2×). The solvent was removed, and the resulting residuewas chromatographered using ethyl acetate/methanol (20:1-10:1) to givethe title compound (870 mg, 31%). MS (DCI/NH₃) m/z 217 (M+1)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.63 (m, 2H) 1.86 (m, 2H) 2.11 (s, 3H) 2.18 (m,2H) 2.48 (m, 2H) 4.55 (m, 1H) 7.00 (td, J=7.67, 0.61 Hz, 1H) 7.23 (d,J=8.59 Hz, 1H) 7.56 (td, J=10.13, 7.36, 1.84 Hz, 1H) 7.63 (dd, J=7.67,1.84 Hz, 1H).

EXAMPLE 84B 2-(1-Methyl-piperidin-4-yloxy)-benzylamine

The title compound was prepared using the method of Example 78B,substituting the product of Example 84A for the product of Example 78A.MS (DCI/NH₃) m/z 221 (M+1)⁺.

EXAMPLE 84C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-4-yloxy)-benzyl]-amine

The product of Example 84B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 433 (M)⁺, 435 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.65 (m, 2H) 1.88 (m, 2H) 2.05 (s, 1H) 2.15(s, 3H) 2.20 (m, 2H) 2.54 (m, 1H) 4.41 (m, 1H) 4.48 (d, J=5.83 Hz, 2H)6.86 (td, J=7.36, 0.61 Hz, 1H) 7.00 (d, J=7.98 Hz, 1H) 7.19 (m, 2H) 7.41(t, J=5.83 Hz, 1H) 7.60 (t, J=7.98 Hz, 1H) 7.69 (dd, J=7.98, 1.53 Hz,1H) 7.93 (dd, J=7.98, 1.53 Hz, 1H).

EXAMPLE 85[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-4-yloxy)-pyridin-3-ylmethyl]-amineEXAMPLE 85A 2-(1-Methyl-piperidin-4-Yloxy)-nicotinonitrile

To a mixture of 2-fluoro-nicotinonitrile (400 mg, 3.3 mmol) and1-methyl-piperidin-4-ol (380 mg, 3.3 mmol) in N,N-dimethylformamide (30mL) was added NaH (60%) (160 mg, 4.0 mmol) in portions. The reaction wasstirred overnight at rt. The mixture was poured into water, andextracted with ethyl acetate (2×). The solvent was removed, and theresulting residue was chromatographed using ethyl acetate/methanol (8:1)to give the title compound (210 mg, 29%). MS (DCI/NH₃) m/z 218 (M+1)+

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.73 (m, 2H) 1.96 (m, 2H) 2.18 (s, 3H)2.22 (m, 2H) 2.59 (m, 2H) 5.15 (m, 1H) 7.15 (dd, J=7.67, 5.22 Hz, 1H)8.24 (dd, J=7.67, 2.15 Hz, 1H) 8.44 (dd, J=4.91, 1.84 Hz, 1H).

EXAMPLE 85B C-[2-(1-Methyl-piperidin-4-yloxy)-pyridin-3-yl]-methylamine

The title compound was prepared using the method of Example 78B,substituting the product of Example 85A for the product of Example 78A.MS (DCI/NH₃) m/z 222 (M+1)⁺.

EXAMPLE 85C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-4-yloxy)-pyridin-3-ylmethyl]-amine

The product from Example 85B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 434 (M)⁺, 436 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.69 (m, 2H) 1.92 (m, 2H) 2.07 (s, 1H) 2.19(s, 3H) 2.25 (m, 2H) 2.58 (m, 1H) 4.43 (d, J=5.83 Hz, 2H) 5.08 (m, 1H)6.93 (dd, J=7.36, 4.91 Hz, 1H) 7.51 (t, J=5.52 Hz, 1H) 7.56 (dd, J=7.06,1.84 Hz, 1H) 7.62 (t, J=7.98 Hz, 1H) 7.73 (dd, J=7.98, 1.53 Hz, 1H) 7.95(dd, J=8.29, 1.53 Hz, 1H) 8.04 (dd, J=4.91, 1.84 Hz, 1H).

EXAMPLE 86[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-3-yloxy)-pyridin-3-ylmethyl]-amineEXAMPLE 86A 2-(1-Methyl-piperidin-3-yloxy)-nicotinonitrile

2-Fluoro-nicotinonitrile was reacted with 1-methyl-piperidin-3-olaccording to the method of Example 85A to provide the title compound. MS(DCI/NH₃) m/z 218 (M+1)⁺.

EXAMPLE 86B C-[2-(1-Methyl-piperidin-3-yloxy)-pyridin-3-yl]-methylamine

The product from Example 86A according to the method of Example 78Bprovided the title compound. MS (DCI/NH₃) m/z 222 (M+1)⁺.

EXAMPLE 86C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-3-yloxy)-pyridin-3-ylmethyl]-amine

The product from Example 86B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 434 (M)⁺, 436 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.38 (m, 1H) 1.52 (m, 1H) 1.71 (m, 1H) 1.93(m, 2H) 2.06 (m, 2H) 2.18 (s, 3H) 2.85 (d, J=10.74 Hz, 1H) 4.40 (d,J=5.52 Hz, 2H) 5.07 (m, 1H) 6.93 (dd, J=7.36, 5.22 Hz, 1H) 7.49 (t,J=5.52 Hz, 1H) 7.56 (dd, J=7.06, 1.84 Hz, 1H) 7.62 (t, J=7.98 Hz, 1H)7.73 (dd, J=7.98, 1.53 Hz, 1H) 7.95 (dd, J=7.98, 1.53 Hz, 1H) 8.04 (dd,J=4.91, 1.84 Hz, 1H).

EXAMPLE 87[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-pyrrolidin-3-yloxy)-pyridin-3-ylmethyl]-amineEXAMPLE 87A 2-(1-Methyl-pyrrolidin-3-yloxy)-nicotinonitrile

2-Fluoro-nicotinonitrile was reacted with 1-methyl-pyrrolidin-3-olaccording to the method of Example 85A to provide the title compound. MS(DCI/NH₃) m/z 204 (M+1)⁺.

EXAMPLE 87B C-[2-(1-Methyl-pyrrolidin-3-yloxy)-pyridin-3-yl]-methylamine

The product from Example 87A according to the method of Example 78Bprovided the title compound. MS (DCI/NH₃) m/z 208 (M+1)⁺.

EXAMPLE 87C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-pyrrolidin-3-yloxy)-pyridin-3-ylmethyl]-amine

The product from Example 87B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 420 (M)⁺, 422 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.82 (m, 1H) 2.26 (m, 1H) 2.31 (s, 3H) 2.45(dd, J=14.12, 7.36 Hz, 1H) 2.66 (dd, J=10.74, 2.76 Hz, 1H) 2.72 (dd,J=15.04, 7.98 Hz, 1H) 2.88 (dd, J=10.74, 6.14 Hz, 1H) 4.07 (brs, 1H)4.42 (d, J=5.83 Hz, 2H) 5.39 (m, 1H) 6.94 (dd, J=7.06, 4.91 Hz, 1H) 7.54(t, J=5.52 Hz, 1H) 7.57 (dd, J=7.06, 1.84 Hz, 1H) 7.62 (t, J=7.98 Hz,1H) 7.74 (dd, J=7.98, 1.53 Hz, 1H) 7.94 (dd, J=8.29, 1.53 Hz, 1H) 8.04(dd, J=4.91, 1.84 Hz, 1H).

EXAMPLE 88[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-pyridin-3-ylmethyl]-amineEXAMPLE 88A 4-Hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acidtert-butyl ester

To the solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (3.5 g, 16.5 mmol) was added BH₃-tetrahydrofuran (1Min tetrahydrofuran) (32.9 mL, 32.9 mmol). The reaction was stirred at rtovernight. Quenched with water, the mixture was extracted with ethylacetate (2×), The organic layers were combined and washed with saturatedsodium bicarbonate, brine, dried. The resulting residue waschromatographered using ethyl acetate to give the title compound (2.66g, 74%). MS (DCI/NH₃) m/z 218 (M+1)⁺.

EXAMPLE 88B 2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acidtert-butyl ester

A mixture of the product from Example 88A (2.66 g, 12.3 mmol) andtriphenyl phosphine (3.9 g, 13.5 mmol) in dichloromethane (125 mL) wasadded diisopropyl azodicarboxylate (2.66 mL, 13.5 mmol) dropwise at 0°C. The reaction mixture was allowed to warm up to rt for 12 hr. Thesolution was concentrated to dryness and the residue was chromatographedusing hexane/ethyl acetate (20:1-5:1) to give the title compound (1.57g, 64%). MS (DC/NH₃) m/z 200 (M+1)⁺.

EXAMPLE 88C 2-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-nicotinonitrile

The product from Example 88B (1.57 g, 7.9 mmol) in dichloromethane (25mL) was treated with trifluoroacetic acid (5 mL) for 30 min at rt. Thereaction mixture was concentrated to dryness. To the residue was added2-fluoro-nicotinonitrile (1.0 g, 8.19 mmol) and diisopropyl ethylamine(3.2 mL) in tetrahydrofuran (8 mL). The reaction mixture was heated at115° C. for 10 min under microwave condition. The mixture wasconcentrated to dryness, and the residue was chromatographed usinghexane/ethyl acetate (9:1-6:1) to give the title compound (806 mg, 51%).MS (DCI/NH₃) m/z 202 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.98 (s, 2H)3.67 (d, J=10.13 Hz, 1H) 3.91 (dd, J=7.98, 1.53 Hz, 1H) 3.96 (m, 2H)4.69 (s, 1H) 5.16 (s, 1H) 6.64 (dd, J=7.67, 4.91 Hz, 1H) 7.71 (dd,J=7.36, 1.84 Hz, 1H) 8.26 (dd, J=4.60, 1.84 Hz, 1H)

EXAMPLE 88DC-[2-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-pyridin-3-yl]methylamine

The product from Example 88C according to the method of Example 78Bprovided the title compound. MS (DCI/NH₃) m/z 206 (M+1)⁺.

EXAMPLE 88E[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-pyridin-3-ylmethyl]-amine

The product from Example 88D was reacted2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 418 (M)⁺, 420 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.77 (dt, J=9.67, 0.94 Hz, 1H) 1.82 (dd,J=9.67, 2.18 Hz, 1H) 3.25 (d, J=9.05 Hz, 1H) 3.61 (dd, J=9.05, 1.56 Hz,1H) 3.77 (dd, J=7.18, 1.56 Hz, 1H) 3.93 (d, J=7.18 Hz, 1H) 4.34 (dd,J=15.60, 5.30 Hz, 1H) 4.43 (dd, J=15.60, 5.62 Hz, 1H) 4.56 (s, 1H) 4.66(s, 1H) 6.76 (dd, J=7.18, 4.68 Hz, 1H) 7.50 (dd, J=7.49, 1.56 Hz, 1H)7.59 (t, J=4.68 Hz, 1H) 7.61 (t, J=7.80 Hz, 2H) 7.71 (dd, J=7.80, 1.56Hz, 1H) 7.94 (dd, J=8.11, 1.56 Hz, 1H) 8.02 (dd, J=4.99, 1.87 Hz, 1H).Anal. Calcd for C₁₈H₁₇N₇Cl₂O: C, 51.69; H, 4.10; N, 23.44. Found: C,51.55; H, 4.21; N, 21.62.

EXAMPLE 89[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-methyl-3-(pyridin-2-yloxy)-benzyl]-amineEXAMPLE 89A 3-Hydroxymethyl-2-methyl-phenol

3-Hydroxy-2-methyl-benzoic acid (1.0 g, 7.2 mmol) in tetrahydrofuran (80mL) was treated with dropwise added BH₃-tetrahydrofuran (1M intetrahydrofuran)(10 mL). The reaction mixture was stirred at rtovernight. Quenched with 10% NaOH, the mixture was adjusted pH to 7 with10% HCl and extracted with isopropanol/dichloromethane (1:3) (2×), Theorganic layers were combined and washed with water, brine, dried toafford the title compound (795 mg, 80%). MS (DCI/NH₃) m/z 139 (M+1)⁺.

EXAMPLE 89B [2-Methyl-3-(pyridin-2-yloxy)-phenyl]-methanol

A mixture of the product from Example 89A (740 mg, 5.36 mmol),2-fluoropyridine (565 mg, 5.92 mmol) and K₂CO₃ (600 mg) inN,N-dimethylformamide (30 mL) was heated at 150° C. for 3 hr. Thereaction mixture was poured into water, and extracted with ethyl acetate(2×). The solvent was removed, and the resulting residue waschromatographed using Hexane/ethyl acetate (6:1-4:1) to give the titlecompound (190 mg, 16%). MS (DCI/NH₃) m/z 216 (M+1)⁺.

EXAMPLE 89C 2-(3-Azidomethyl-2-methyl-phenoxy)-pyridine

The title compound was prepared using the procedure as described inExample 77A, substituting the product from Example 89B for3-(pyrimidin-2-yloxy)-phenyl-methanol. MS (DCI/NH₃) m/z 241 (M+1)⁺.

EXAMPLE 89D 2-Methyl-3-(pyridin-2-yloxy)-benzylamine

The product from Example 89C followed the same procedure as describedfor Example 77B to give the title compound. MS (DCI/NH₃) m/z 215 (M+1)⁺.

EXAMPLE 89E[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-methyl-3-(pyridin-2-yloxy)-benzyl]-amine

The product from Example 89D was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 427 (M)⁺, 429 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.06 (s, 3H) 4.51 (d, J=5.62 Hz, 2H) 6.96(dd, J=7.18, 2.81 Hz, 1H) 6.99 (dt, J=8.42, 0.94 Hz, 1H) 7.08 (ddd,J=7.18, 4.99, 0.94 Hz, 1H) 7.19 (dd, J=12.48, 7.80 Hz, 1H) 7.18 (s, 1H)7.62 (m, 2H) 7.72 (dd, J=8.11, 1.56 Hz, 1H) 7.83 (ddd, J=9.05, 7.18,2.18 Hz, 1H) 7.94 (dd, J=8.11, 1.25 Hz, 1H) 8.09 (ddd, J=4.68, 1.87,0.62 Hz, 1H).

EXAMPLE 902-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-benzonitrileEXAMPLE 90A 2-Azidomethyl-benzonitrile

A mixture of 2-bromomethyl-benzonitrile (300 mg, 1.53 mmol) and sodiumazide (129 mg, 1.99 mmol) in acetone was stirred overnight at rt. Thesolvent was removed, and the resulting residue was chromatographeredusing hexane/ethyl acetate (6:1) to give the title compound (212 mg,88%). MS (DCI/NH₃) m/z 176 (M+18)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.69(s, 2H) 7.58 (td, J=7.67, 1.23 Hz, 1H) 7.66 (d, J=7.67 Hz, 1H) 7.76 (td,J=7.67, 1.23 Hz, 1H) 7.91 (dd, J=7.67, 1.53 Hz, 1H).

EXAMPLE 90B 2-Aminomethyl-benzonitrile

The product from Example 90A followed the same procedure as describedfor Example 77B to give the title compound. MS (DCI/NH₃) m/z 133 (M+1)⁺.

EXAMPLE 90C2-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-benzonitrile

The product from Example 90B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 345 (M)⁺, 347 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.67 (d, J=5.62 Hz, 2H) 7.48 (t, J=7.80 Hz,1H) 7.56 (d, J=8.11 Hz, 1H) 7.63 (t, J=8.11 Hz, 1H) 7.69 (td, J=7.80,1.25 Hz, 1H) 7.73 (dd, J=8.11, 1.56 Hz, 1H) 7.83 (dd, J=7.49, 0.94 Hz,1H) 7.89 (t, J=5.62 Hz, 1H) 7.96 (dd, J=8.42, 1.56 Hz, 1H).

EXAMPLE 91[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(2-methyl-pyridin-3-yloxy)-pyridin-3-ylmethyl]-amineEXAMPLE 91A 2-(2-Methyl-pyridin-3-yloxy)-nicotinonitrile

2-Fluoro-nicotinonitrile was reacted with 2-methyl-pyridin-3-olaccording to the method of Example 85A to provide the title compound. MS(DCI/NH₃) m/z 212 (M+1)⁺.

EXAMPLE 91B C-[2-(2-Methyl-pyridin-3-yloxy)-pyridin-3-yl]-methylamine

The title compound was prepared using the procedure as described inExample 78B, substituting the product from Example 91A for the productfrom Example 78A. MS (DCI/NH₃) m/z 216 (M+1)⁺.

EXAMPLE 91C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(2-methyl-pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine

The product from Example 91B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 428 (M)⁺, 430 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H) 4.64 (d, J=5.62 Hz, 2H) 7.12(dd, J=7.18, 4.68 Hz, 1H) 7.30 (dd, J=8.11, 4.68 Hz, 1H) 7.51 (dd,J=8.11, 1.25 Hz, 1H) 7.63 (t, J=8.11 Hz, 1H) 7.73 (dd, J=8.11, 1.56 Hz,1H) 7.76 (t, J=5.62 Hz, 1H) 7.80 (dd, J=7.18, 1.87 Hz, 1H) 7.95 (dd,J=8.11, 1.56 Hz, 1H) 7.97 (dd, J=4.68, 1.87 Hz, 1H) 8.32 (dd, J=4.68,1.25 Hz, 1H).

EXAMPLE 92[2-(5-Chloro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amineEXAMPLE 92A 2-(5-Chloro-pyridin-3-yloxy)-nicotinonitrile

2-Fluoro-nicotinonitrile was reacted with 5-chloro-pyridin-3-olaccording to the method of Example 85A to provide the title compound. MS(DCI/NH₃) m/z 232 (M)⁺, 234 (M+2)⁺.

EXAMPLE 92B C-[2-(5-Chloro-pyridin-3-yloxy)-pyridin-3-yl]-methylamine

The title compound was prepared using the procedure as described inExample 78B, substituting the product from Example 92A for the productfrom Example 78A. MS (DCI/NH₃) m/z 236 (M)⁺, 238 (M+2)⁺.

EXAMPLE 92C[2-(5-Chloro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine

The product from Example 92B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 448 (M)⁺, 450 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.62 (d, J=5.52 Hz, 2H) 7.20 (dd, J=7.36,4.91 Hz, 1H) 7.62 (t, J=8.29 Hz, 1H) 7.74 (m, 2H) 7.84 (dd, J=7.36, 1.53Hz, 1H) 7.89 (t, J=2.15 Hz, 1H) 7.96 (dd, J=8.29, 1.53 Hz, 1H) 8.06 (dd,J=4.91, 1.53 Hz, 1H) 8.46 (d, J=2.15 Hz, 1H) 8.51 (d, J=2.15 Hz, 1H).

EXAMPLE 93[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[6-methyl-2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amineEXAMPLE 93A 6-Methyl-2-(pyridin-3-yloxy)-nicotinonitrile

2-chloro-6-methyl-nicotinonitrile was reacted with pyridin-3-olaccording to the method of Example 85A to provide the title compound. MS(DCI/NH₃) m/z 212 (M+1)⁺.

EXAMPLE 93B C-[6-Methyl-2-(pyridin-3-yloxy)-pyridin-3-yl]-methylamine

The title compound was prepared using the procedure as described inExample 78B, substituting the product from Example 93A for the productfrom Example 78A. MS (DCI/NH₃) m/z 216 (M+1)⁺.

EXAMPLE 93C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[6-methyl-2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine

The product from Example 93B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 428 (M)⁺, 430 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H) 4.57 (d, J=5.52 Hz, 2H) 7.01(d, J=7.36 Hz, 1H) 7.46 (dd, J=8.29, 4.60 Hz, 1H) 7.59 (m, 1H) 7.62 (d,J=7.98 Hz, 1H) 7.70 (m, 3H) 7.94 (dd, J=8.29, 1.53 Hz, 1H) 8.41 (dd,J=4.91, 1.23 Hz, 1H) 8.43 (d, J=2.76 Hz, 1H).

EXAMPLE 94[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amineEXAMPLE 94A 2-(2-Chloro-pyridin-3-yloxy)-nicotinonitrile

2-Fluoro-nicotinonitrile was reacted with 2-chloro-pyridin-3-olaccording to the method of Example 85A to provide the title compound. MS(DCI/NH₃) m/z 232 (M)⁺, 234 (M+2)⁺.

EXAMPLE 94B C-[2-(Pyridin-3-yloxy)-pyridin-3-yl]-methylamine

The title compound was prepared using the procedure as described inExample 78B, substituting the product from Example 94A for the productfrom Example 78A. MS (DCI/NH₃) m/z 202 (M+1)⁺.

EXAMPLE 94C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine

The product from Example 94B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 414 (M)⁺, 416 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.63 (d, J=5.52 Hz, 2H) 7.16 (dd, J=7.36,4.91 Hz, 1H) 7.47 (dd, J=8.29, 4.60 Hz, 1H) 7.62 (m, 2H) 7.75 (m, 2H)7.81 (dd, J=7.06, 1.23 Hz, 1H) 7.96 (dd, J=7.98, 1.23 Hz, 1H) 8.02 (dd,J=4.91, 1.53 Hz, 1H) 8.43 (dd, J=4.91, 1.23 Hz, 1H) 8.44 (d, J=3.07 Hz,1H).

EXAMPLE 95[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(5-fluoro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-amineEXAMPLE 95A 2-(6-Chloro-5-fluoro-pyridin-3-yloxy)-nicotinonitrile

2-Fluoro-nicotinonitrile was reacted with 6-chloro-5-fluoro-pyridin-3-olaccording to the method of Example 85A to provide the title compound. MS(DCI/NH₃) m/z 250 (M)⁺, 252 (M+2)⁺.

EXAMPLE 95B C-[2-(5-Fluoro-pyridin-3-yloxy)-pyridin-3-yl]-methylamine

The title compound was prepared using the procedure as described inExample 78B, substituting the product from Example 95A for the productfrom Example 78A. MS (DCI/NH₃) m/z 220 (M+1)⁺.

EXAMPLE 95C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(5-fluoro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine

The product from Example 95B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 432 (M)⁺, 434 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.62 (d, J=4.30 Hz, 2H) 7.20 (dd, J=7.36,4.91 Hz, 1H) 7.62 (t, J=7.98 Hz, 1H) 7.74 (m, 3H) 7.84 (dd, J=7.36, 1.53Hz, 1H) 7.95 (dd, J=8.29, 1.53 Hz, 1H) 8.06 (dd, J=4.91, 1.53 Hz, 1H)8.38 (brs, 1H) 8.48 (d, J=2.45 Hz, 1H).

EXAMPLE 96[2-(2-Chloro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amineEXAMPLE 96A 2-(2-Chloro-pyridin-3-yloxy)-nicotinonitrile

2-fluoro-nicotinonitrile was reacted with 2-chloro-pyridine followingthe same procedure as described for Example 85A to provide the titlecompound. MS (DCI/NH₃) m/z 232 (M)⁺, 234 (M+2)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.40 (dd, J=7.67, 5.22 Hz, 1H) 7.60 (dd, J=7.98, 4.91 Hz,1H) 8.02 (dd, J=7.98, 1.84 Hz, 1H) 8.39 (d, J=1.84 Hz, 1H) 8.41 (d,J=1.53 Hz, 1H) 8.51 (dd, J=7.67, 1.84 Hz, 1H).

EXAMPLE 96B C-[2-(2-Chloro-pyridin-3-yloxy)-pyridin-3-yl]-methylamine

The product from Example 96A (330 mg, 1.43 mmol) in 20% NH₃-methanol (30mL) was treated with Raney Nickel (165 mg). The mixture was hydrogenatedunder the pressure of 60 psi in a shaker for 4 hr. The solution wasfiltered through a nylon membrane and the filtrate was concentrated toafford the title compound. MS (DCI/NH₃) m/z 236 (M)⁺, 238 (M+2)⁺.

EXAMPLE 96C[2-(2-Chloro-pyridin-3-yloxy)-pyridin-3-ylmethyl]1-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine

The product from Example 96B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 448 (M)⁺, 450 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.66 (d, J=5.83 Hz, 2H) 7.17 (dd, J=7.36,4.91 Hz, 1H) 7.54 (dd, J=7.98, 4.91 Hz, 1H) 7.63 (t, J=8.29 Hz, 1H) 7.76(m, 2H) 7.83 (td, J=7.98, 1.53 Hz, 2H) 7.96 (dd, J=8.29, 1.53 Hz, 1H)8.00 (dd, J=4.91, 1.84 Hz, 1H) 8.32 (dd, J=4.60, 1.53 Hz, 1H)

EXAMPLE 97[2-(6-Chloro-5-fluoro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amineEXAMPLE 97A1-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]pyridin-3-yl}methanamine

The title compound was prepared according to the method of Example 96B,substituting the product from Example 95A for the product of Example96A. MS (DCI/NH₃) m/z 254 (M)⁺, 256 (M+2)⁺.

EXAMPLE 97B[2-(6-Chloro-5-fluoro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine

The product from Example 97A was reacted with2,3-dichlorophenylisothiocyanate, according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 466 (M)⁺, 468 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.62 (d, J=5.52 Hz, 2H) 7.22 (dd, J=7.36,4.91 Hz, 1H) 7.62 (t, J=7.98 Hz, 1H) 7.75 (m, 2H) 7.85 (dd, J=7.36, 1.53Hz, 1H) 7.96 (dd, J=7.98, 1.23 Hz, 1H) 8.02 (dd, J=9.51, 2.46 Hz, 1H)8.06 (dd, J=4.91, 1.53 Hz, 1H) 8.27 (d, J=2.45 Hz, 1H).

EXAMPLE 98[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[5-fluoro-2-(pyridin-2-yloxy)-benzyl]-amineEXAMPLE 98A 5-Fluoro-2-hydroxy-benzaldehyde oxime

A solution of sodium acetate trihydrate (1.94 g, 14.28 mmol) in H₂O (8mL) was added to a warm solution of 5-fluoro-2-hydroxy-benzaldehyde (1.0g, 7.14 mmol) and NH₂OH HCl (992 mg, 14.28 mmol) in 80% ethanol (30 mL).The reaction mixture was refluxed for 3 hr. Removal of ethanol, themixture was cooled to rt, collected the precipitate and washed withwater, dried to afford the title compound (920 mg, 83%). MS (DCI/NH₃)m/z 217 (M+62)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 6.89 (dd, J=9.15, 4.88Hz, 1H) 7.07 (td, J=8.54, 3.05 Hz, 1H) 7.29 (dd, J=9.46, 3.05 Hz, 1H)8.30 (s, 1H) 10.02 (brs, 1H) 11.46 (brs, 1H).

EXAMPLE 98B 5-Fluoro-2-hydroxy-benzonitrile

The product from Example 98A (920 mg, 5.93 mmol) in acetic anhydride (15mL) μanhydride. A solution of KOH (2 g) in H₂O (10 mL) and ethanol (10mL) was added to the above residue. The mixture was heated at 80° C. for2 hr then cooled to rt. The pH of the solution was adjusted to 7 with 6NHCl, and extracted with isopropanol/dichloromethane (1:3) (2×). Theorganic layers were combined, dried. The resulting residue waschromatographed using hexane/ethyl acetate (5:1) to give the titlecompound (800 mg, 100%). MS (DCI/NH₃) m/z 136 (M+1)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 6.99 (dd, J=9.05, 4.37 Hz, 1H) 7.36 (td, J=9.05, 3.12 Hz,1H) 7.53 (dd, J=8.42, 3.43 Hz, 1H) 11.04 (m, 1H).

EXAMPLE 98C 5-Fluoro-2-(pyridin-2-yloxy)-benzonitrile

The product from Example 98B was reacted with 2-fluoro-pyridinefollowing the procedure as described for Example 78A to give the titlecompound. MS (DCI/NH₃) m/z 215 (M+1)⁺.

EXAMPLE 98D 5-Fluoro-2-(pyridin-2-yloxy)-benzylamine

The product from Example 98C followed the same procedure as describedfor Example 78B to afford the title compound. MS (DCI/NH₃) m/z 219(M+1)⁺.

EXAMPLE 98E[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[5-fluoro-2-(pyridin-2-yloxy)-benzyl]-amine

The product from Example 98D was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 431 (M)⁺, 433 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.38 (d, J=5.93 Hz, 2H) 7.04 (d, J=8.11 Hz,1H) 7.12 (dd, J=7.18, 4.99 Hz, 1H) 7.14 (m, 1H) 7.15 (d, J=1.56 Hz, 1H)7.18 (d, J=9.05 Hz, 1H) 7.59 (dd, J=5.93, 4.37 Hz, 1H) 7.62 (d, J=7.80Hz, 1H) 7.66 (dd, J=7.80, 1.56 Hz, 1H) 7.86 (td, J=8.11, 1.87 Hz, 1H)7.94 (dd, J=8.11, 1.87 Hz, 1H) 8.10 (dd, J=4.99, 1.87 Hz, 1H).

EXAMPLE 99[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[5-fluoro-2-(pyridin-3-yloxy)-benzyl]-amineEXAMPLE 99A 2-(2-Chloro-pyridin-3-yloxy)-5-fluoro-benzonitrile

2,5-Difluoro-benzonitrile was reacted with 2-chloropyridin-3-olaccording to the method of Example 78A to provide the title compound. MS(DCI/NH₃) m/z 249 (M)⁺, 251 (M+2)⁺.

EXAMPLE 99B 5-Fluoro-2-(pyridin-3-yloxy)-benzylamine

The product from Example 99A followed the same procedure as describedfor Example 78B to afford the title compound. MS (DCI/NH₃) m/z 219(M+1)⁺.

EXAMPLE 99C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[5-fluoro-2-(pyridin-3-yloxy)-benzyl]-amine

The product from Example 99B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 431 (M)⁺, 433 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.50 (d, J=5.62 Hz, 2H) 7.04 (dd, J=9.05,4.68 Hz, 1H) 7.16 (td, J=8.73, 3.12 Hz, 1H) 7.25 (dd, J=9.36, 3.12 Hz,1H) 7.34 (ddd, J=8.42, 3.12, 1.56 Hz, 1H) 7.41 (ddd, J=8.42, 4.37, 0.62Hz, 1H) 7.61 (t, J=8.11 Hz, 1H) 7.66 (m, 2H) 7.95 (dd, J=8.11, 1.56 Hz,1H) 8.33 (d, J=2.81 Hz, 1H) 8.34 (dd, J=4.68, 1.25 Hz, 1H).

EXAMPLE 100[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[5-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzyl]-amineEXAMPLE 100A 5-Fluoro-2-(2,2,2-trifluoro-ethoxy)-benzonitrile

2,5-difluoro-benzonitrile was reacted with 2,2,2-trifluoro-ethanolaccording to the method of Example 84A to provide the title compound. MS(DCI/NH₃) m/z 220 (M+1)⁺.

EXAMPLE 100B 5-Fluoro-2-(2,2,2-trifluoro-ethoxy)-benzylamine

The product from Example 100A followed the same procedure as describedfor Example 78B to afford the title compound. MS (DCI/NH₃) m/z 224(M+1)⁺.

EXAMPLE 100C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[5-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzyl]-amine

The product from Example 100B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 436 (M)⁺, 438 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.47 (d, J=5.93 Hz, 2H) 4.77 (q, J=8.74 Hz,2H) 7.04 (dd, J=9.36, 3.12 Hz, 1H) 7.12 (m, 2H) 7.58 (t, J=5.62 Hz, 1H)7.62 (t, J=8.11 Hz, 1H) 7.75 (dd, J=7.80, 1.56 Hz, 1H) 7.95 (dd, J=8.42,1.56 Hz, 1H).

EXAMPLE 101[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4,5-difluoro-2-(pyridin-2-yloxy)-benzyl]-amineEXAMPLE 101A 2-(2-Bromo-4,5-difluoro-phenoxy)-pyridine

A mixture of 2-(2-bromo-4,5-difluoro-phenoxy)-pyridine (800 mg, 3.83mmol), 2-fluoro-pyridine (371 mg, 3.83 mmol) and K₂CO₃ (435 mg, 4.6mmol) in N,N-dimethylformamide (5 mL) was heated at 120° C. overnight.The reaction mixture was poured into water, and extracted with ethylacetate (2×). The solvent was removed, and the resulting residue waschromatographed using hexane/ethyl acetate (7:1) to give the titlecompound (448 mg, 41%). MS (DCI/NH₃) m/z 286 (M)⁺, 288 (M+2)⁺. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.01 (d, J=8.29 Hz, 1H) 7.03 (dd, J=6.44, 4.91Hz, 1H) 7.10 (dd, J=10.43, 7.36 Hz, 1H) 7.47 (dd, J=9.21, 8.29 Hz, 1H)7.74 (td, J=9.21, 1.84 Hz, 1H) 8.13 (dd, J=4.91, 1.23 Hz, 1H).

EXAMPLE 101B 4,5-Difluoro-2-(pyridin-2-yloxy)-benzonitrile

A flask was charged with the product from Example 101A (440 mg, 1.54mmol), Zn(CN)₂ (99 mg, 0.85 mmol) and Pd(PPh₃)₄ (178 mg, 0.154 mmol) inN,N-dimethylformamide (2 mL), and was purged with nitrogen. The reactionmixture was heated at 120° C. overnight. After cooling to roomtemperature, the mixture was diluted with ethyl acetate and washed withwater, dried (MgSO₄), filtered and concentrated. The resulting residuewas chromatographed using hexane/ethyl acetate (7:1) to give the titlecompound (151 mg, 42%). MS (DCI/NH₃) m/z 233 (M+1)⁺, ¹H NMR (400 MHz,CDCl₃) δ ppm 7.11 (m, 2H) 7.23 (dd, J=10.74, 6.75 Hz, 1H) 7.50 (t,J=8.29 Hz, 1H) 7.79 (td, J=8.29, 2.15 Hz, 1H) 8.15 (dd, J=4.91, 0.92 Hz,1H).

EXAMPLE 101C 4,5-Difluoro-2-(pyridin-2-yloxy)-benzylamine

The product from Example 101B followed the same procedure as describedfor Example 78B to afford the title compound. MS (DCI/NH₃) m/z 237(M+1)⁺.

EXAMPLE 101D[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4,5-difluoro-2-(pyridin-2-yloxy)-benzyl]-amine

The product from Example 101C was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 449 (M)⁺, 451 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.35 (d, J=5.93 Hz, 2H) 7.06 (d, J=8.11 Hz,1H) 7.15 (ddd, J=7.18, 4.99, 0.94 Hz, 1H) 7.35 (dd, J=11.23, 7.18 Hz,1H) 7.40 (dd, J=11.54, 9.36 Hz, 1H) 7.56 (m, 1H) 7.60 (d, J=8.11 Hz, 1H)7.64 (dd, J=7.80, 1.56 Hz, 1H) 7.86 (td, J=8.42, 1.87 Hz, 1H) 7.93 (dd,J=8.11, 1.56 Hz, 1H) 8.11 (dd, J=4.99, 1.25 Hz, 1H).

EXAMPLE 102[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(pyridin-2-yloxy)-benzyl]-amineEXAMPLE 102A 2-(2-Bromo-5-fluoro-phenoxy)-pyridine

2-Bromo-5-fluoro-phenol was reacted with 2-fluoro-pyridine according tothe method of Example 101A to provide the title compound. MS (DCI/NH₃)m/z 268 (M)⁺, 270 (M+2)⁺.

EXAMPLE 102B 4-Fluoro-2-(pyridin-2-yloxy)-benzonitrile

The product from Example 102A followed the same procedure as describedfor Example 101B to afford the title compound. MS (DCI/NH₃) m/z 215(M+1)⁺.

EXAMPLE 102C 4-Fluoro-2-(pyridin-2-yloxy)-benzylamine

The product from Example 102B followed the same procedure as describedfor Example 78B to afford the title compound. MS (DCI/NH₃) m/z 219(M+1)⁺.

EXAMPLE 102D[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(pyridin-2-yloxy)-benzyl]-amine

The product from Example 102C was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 431 (M)⁺, 433 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.37 (d, J=5.80 Hz, 2H) 7.06 (m, 3H) 7.16(dd, J=6.41, 4.88 Hz, 1H) 7.43 (dd, J=8.24, 6.71 Hz, 1H) 7.56 (m, 3H)7.88 (td, J=8.54, 2.14 Hz, 1H) 7.93 (dd, J=7.02, 2.44 Hz, 1H) 8.13 (dd,J=5.19, 2.14 Hz, 1H).

EXAMPLE 103[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(4-fluoro-2-pyridin-2-yl-benzyl)-amineEXAMPLE 103A (4-Fluoro-2-pyridin-2-yl-benzyl)-carbamic acid tert-butylester

A round bottle flask was charged with (2-boronicacid-4-fluoro-benzyl)-carbamic acid tert-butyl ester (100 mg, 0.37mmol), 2-chloro-pyridine (42 mg, 0.37 mmol), CsF (202 mg, 1.11 mmol) andPd(PPh₃)₄ (43 mg, 0.037 mmol) in 1,2-dimethoxyethane (DME)/methanol(2:1) (10 mL), and was purged with nitrogen. The reaction mixture washeated at 85° C. overnight. After cooling to room temperature, themixture was diluted with ethyl acetate and washed with water, dried(MgSO₄), filtered and concentrated. The resulting residue waschromatographed using hexane/ethyl acetate (6:1) to give the titlecompound (83 mg, 74%). MS (DCI/NH₃) m/z 303 (M+1)⁺, ¹H NMR (500 MHz,CDCl₃) δ ppm 1.44 (s, 9H) 4.21 (d, J=4.68 Hz, 2H) 5.90 (brs, 2H) 7.08(td, J=8.42, 2.81 Hz, 1H) 7.14 (dd, J=9.36, 2.50 Hz, 1H) 7.30 (ddd,J=7.80, 4.99, 1.25 Hz, 1H) 7.48 (d, J=7.80 Hz, 1H) 7.55 (t, J=6.55 Hz,1H) 7.80 (td, J=7.80, 1.87 Hz, 1H) 8.70 (d, J=4.37 Hz, 1H).

EXAMPLE 103B[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(4-fluoro-2-pyridin-2-yl-benzyl)-amine

The product from Example 103A was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 80Bprovided the title compound. MS (DCI/NH₃) m/z 415 (M)⁺, 417 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.57 (d, J=5.49 Hz, 2H) 7.27 (td, J=8.54,2.75 Hz, 1H) 7.31 (dd, J=9.76; 2.75 Hz, 1H) 7.42 (ddd, J=7.32, 4.58,0.61 Hz, 1H) 7.51 (dd, J=8.85, 6.10 Hz, 1H) 7.55 (t, J=5.80 Hz, 1H) 7.63(m, 2H) 7.74 (dd, J=7.93, 1.53 Hz, 1H) 7.93 (m, 1H) 7.96 (dd, J=8.24,1.53 Hz, 1H) 8.60 (d, J=4.88 Hz, 1H).

EXAMPLE 104[6-Chloro-5-fluoro-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amineEXAMPLE 104A6-Chloro-5-fluoro-2-(2,2,2-trifluoro-ethoxy)-nicotinonitrile

A mixture of 2,6-dichloro-5-fluoro-nicotinonitrile (900 mg, 5.7 mmol),2,2,2-trifluoro-ethanol (570 mg, 5.7 mmol), and NaH (60%) (273 mg, 6.8mmol) in N,N-dimethylformamide (15 mL) was heated at 120° C. overnight.The reaction mixture was poured into water, and extracted with ethylacetate (2×). The solvent was removed to give the title compound (1100mg, 76%). MS (DCI/NH₃) m/z 255 (M)⁺, 257 (M+2)⁺.

EXAMPLE 104BC-[6-Chloro-5-fluoro-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-methylamine

The product from Example 104A according to the method of Example 96Bprovided the title compound. MS (DCI/NH₃) m/z 259 (M)⁺.

EXAMPLE 104C[6-Chloro-5-fluoro-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine

The product from Example 104B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 472 (M)⁺, 474 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.49 (d, J=5.62 Hz, 2H) 5.06 (q, J=8.73 Hz,2H) 7.63 (t, J=8.11 Hz, 1H) 7.74 (t, J=5.62 Hz, 1H) 7.78 (dd, J=8.11,1.56 Hz, 1H) 7.86 (d, J=10.29 Hz, 1H) 7.96 (dd, J=8.11, 1.25 Hz, 1H).

EXAMPLE 105[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(3-fluoro-pyridin-2-yl)-benzyl]-amineEXAMPLE 105A [4-Fluoro-2-(3-fluoro-pyridin-2-yl)-benzyl]-carbamic acidtert-butyl ester

(2-boronic acid-4-fluoro-benzyl)-carbamic acid tert-butyl ester wasreacted with 2-chloro-3-fluoro-pyridine according to the method ofExample 103A to provide the title compound. MS (DCI/NH₃) m/z 321 (M+1)⁺.

EXAMPLE 105B[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(3-fluoro-pyridin-2-yl)-benzyl]-amine

The product from Example 105A was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 80Bto provide the title compound. MS (DCI/NH₃) m/z 433 (M)⁺, 435 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.84 (d, J=5.80 Hz, 2H) 7.68 (dd, J=9.46,1.83 Hz, 1H) 7.73 (td, J=8.54, 2.75 Hz, 1H) 7.92 (m, 3H) 8.00 (m, 1H)8.01 (d, J=1.83 Hz, 1H) 8.28 (td, J=8.54, 1.22 Hz, 1H) 8.34 (dd, J=5.49,3.97 Hz, 1H) 8.91 (d, J=4.58 Hz, 1H).

EXAMPLE 106[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(6-fluoro-pyridin-3-yl)-benzyl]-amineEXAMPLE 106A [4-Fluoro-2-(6-fluoro-pyridin-3-yl)-benzyl]-carbamic acidtert-butyl ester

(2-boronic acid-4-fluoro-benzyl)-carbamic acid tert-butyl ester wasreacted with 5-bromo-2-fluoro-pyridine according to the method ofExample 103A to provide the title compound. MS (DCI/NH₃) m/z 321 (M+1)⁺.

EXAMPLE 106B[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(6-fluoro-pyridin-3-yl)-benzyl]-amine

The product from Example 106A was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 80Bto provide the title compound. MS (DCI/NH₃) m/z 433 (M)⁺, 435 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.36 (d, J=5.49 Hz, 2H) 7.19 (dd, J=9.46,2.75 Hz, 1H) 7.28 (m, 2H) 7.53 (dd, J=8.54, 5.80 Hz, 1H) 7.62 (m, 3H)7.94 (dd, J=7.93, 1.83 Hz, 1H) 8.08 (td, J=8.24, 2.44 Hz, 1H) 8.29 (d,J=2.14 Hz, 1H).

EXAMPLE 107[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(5,6-difluoro-pyridin-3-yl)-4-fluoro-benzyl]-amineEXAMPLE 107A [2-(5,6-Difluoro-pyridin-3-yl)-4-fluoro-benzyl]-carbamicacid tert-butyl ester

(2-Boronic acid-4-fluoro-benzyl)-carbamic acid tert-butyl ester wasreacted with 5-chloro-2,3-difluoro-pyridine according to the method ofExample 103A to provide the title compound. MS (DCI/NH₃) m/z 339 (M+1)⁺.

EXAMPLE 107B[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(5,6-difluoro-pyridin-3-yl)-4-fluoro-benzyl]-amine

The product from Example 107A was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 80Bto provide the title compound. MS (DCI/NH₃) m/z 451 (M)⁺, 453 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.40 (d, J=5.30 Hz, 2H) 7.21 (dd, J=9.67,2.81 Hz, 1H) 7.30 (td, J=8.73, 2.81 Hz, 1H) 7.55 (m, 2H) 7.62 (m, 2H)7.93 (dd, J=7.80, 1.87 Hz, 1H) 8.10 (m, 1H) 8.20 (td, J=10.61, 2.18 Hz,1H).

EXAMPLE 108[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4,5-difluoro-2-(2,2,2-trifluoro-ethoxy)-benzyl]-amineEXAMPLE 108A 1-Bromo-4,5-difluoro-2-trifluoromethoxy-benzene

A mixture of 2-bromo-4,5-difluoro-phenol (1.0 g, 4.8 mmol),1,1,1-trifluoro-2-iodo-ethane (706 mg, 7.2 mmol) and CsF (882 mg, 5.8mmol) in DMSO (20 mL) was heated at 120° C. overnight. The reactionmixture was poured into water, and extracted with ethyl acetate (2×).The solvent was removed, and the resulting residue was chromatographedusing hexane/ethyl acetate (10:1) to give the title compound (697 mg,50%). ¹H NMR (500 MHz, CDCl₃) δ ppm 4.36 (q, J=7.93 Hz, 2H) 6.85 (dd,J=10.98, 7.02 Hz, 1H) 7.43 (t, J=8.85 Hz, 1H).

EXAMPLE 108B 4,5-Difluoro-2-(2,2,2-trifluoro-ethoxy)-benzonitrile

The product from Example 108A followed the same procedure as describedfor Example 101B to give the title compound. MS (DCI/NH₃) m/z 238(M+1)⁺.

EXAMPLE 108C 4,5-Difluoro-2-(2,2,2-trifluoro-ethoxy)-benzylamine

The product from Example 108B followed the same procedure as describedfor Example 78B to afford the title compound. MS (DCI/NH₃) m/z 242(M+1)⁺.

EXAMPLE 108D[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4,5-difluoro-2-(2,2,2-trifluoro-ethoxy)-benzyl]-amine

The product from Example 108C was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 454 (M)⁺, 456 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 4.44 (d, J=5.80 Hz, 2H) 4.83 (q, J=8.85 Hz,2H) 7.28 (dd, J=10.98, 9.46 Hz, 1H) 7.37 (dd, J=12.21, 6.71 Hz, 1H) 7.60(t, J=5.80 Hz, 1H) 7.63 (t, J=8.24 Hz, 1H) 7.77 (dd, J=7.93, 1.53 Hz,1H) 7.96 (dd, J=7.93, 1.22 Hz, 1H).

EXAMPLE 1094-[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-4,5-dihydro-cyclopenta[b]thiophen-6-one

4-Amino-4,5-dihydro-cyclopenta[b]thiophen-6-one was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 366 (M)⁺, 368 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.41 (d, J=6.75 Hz, 1H) 3.46 (d, J=6.75 Hz,1H) 5.45 (m, 1H) 7.21 (d, J=4.91 Hz, 1H) 7.59 (t, J=8.29 Hz, 1H) 7.65(d, J=8.29 Hz, 1H) 7.70 (dd, J=7.98, 1.53 Hz, 1H) 7.92 (dd, J=7.98, 1.23Hz, 1H) 8.25 (d, J=4.60 Hz, 1H).

EXAMPLE 110[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(4-methyl-oxazol-5-ylmethyl)-amineEXAMPLE 110A 4-Methyl-oxazole-5-carbonitrile

4-Methyl-oxazole-5-carboxylic acid amide (200 mg, 1.59 mmol) in POCl₃ (2mL) was refluxed for 7 h. The reaction mixture was poured into water,and extracted with ethyl acetate (2×). The solvent was removed, and theresulting residue was chromatographed using hexane/ethyl acetate (3:1)to give the title compound (240 mg). ¹H NMR (500 MHz, CDCl₃) δ ppm 2.41(s, 3H) 7.93 (s, 1H)

EXAMPLE 110B C-(4-Methyl-oxazol-5-yl)-methylamine

The product from Example 110A followed the same procedure as describedfor Example 78B to afford the title compound. MS (DCI/NH₃) M/z 113(M+1)⁺.

EXAMPLE 110C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(4-methyl-oxazol-5-ylmethyl)-amine

The product from Example 110B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 325 (M)⁺, 327 (M+2)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.14 (s, 3H) 4.49 (d, J=5.62 Hz, 2H) 7.59(t, J=8.11 Hz, 1H) 7.63 (t, J=5.62 Hz, 1H) 7.66 (dd, J=7.80, 1.25 Hz,1H) 7.93 (dd, J=8.11, 1.56 Hz, 1H) 8.16 (s, 1H).

EXAMPLE 111[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(6-fluoro-2-methyl-pyridin-3-ylmethyl)-amineEXAMPLE 111A C-(6-Fluoro-2-methyl-pyridin-3-yl)-methylamine

The title compound was prepared using the procedure as described inExample 78B, substituting 6-fluoro-2-methyl-nicotinonitrile for theproduct of Example 78A. MS (DCI/NH₃) m/z 141 (M+1)⁺.

EXAMPLE 111B[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(6-fluoro-2-methyl-pyridin-3-ylmethyl)-amine

The product from Example 111A was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 353 (M)⁺, 355 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.45 (s, 3H) 4.48 (d, J=5.52 Hz, 2H) 6.95(dd, J=8.29, 2.76 Hz, 1H) 7.61 (t, J=8.29 Hz, 1H) 7.65 (t, J=5.52 Hz,1H) 7.73 (dd, J=7.98, 1.53 Hz, 1H) 7.82 (t, J=8.29 Hz, 1H) 7.95 (dd,J=7.98, 1.23 Hz, 1H).

EXAMPLE 112[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzyl]-amineEXAMPLE 112A 1-Bromo-4-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzene

2-Bromo-5-fluoro-phenol was reacted with 1,1,1-trifluoro-2-iodo-ethaneaccording to the method of Example 108A to provide the title compound.MS (DCI/NH₃) m/z 273 (M)⁺, 275 (M+2)⁺.

EXAMPLE 112B 4-Fluoro-2-(2,2,2-trifluoro-ethoxy)-benzylamine

The product from Example 112A followed the same procedures as describedfor Example 101B and Example 101C to give the title compound. MS(DCI/NH₃) m/z 223 (M+1)⁺.

EXAMPLE 112C[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[4-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzyl]-amine

The product from Example 112B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 436 (M)⁺, 438 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.44 (d, J=5.52 Hz, 2H) 4.82 (q, J=8.59 Hz,2H) 6.85 (td, J=8.59, 2.45 Hz, 1H) 7.09 (dd, J=11.05, 2.45 Hz, 1H) 7.28(t, J=8.29, 7.06 Hz, 1H) 7.52 (t, J=5.83 Hz, 1H) 7.61 (t, J=8.29 Hz, 1H)7.70 (dd, J=7.98, 1.53 Hz, 1H) 7.94 (dd, J=8.29, 1.53 Hz, 1H).

EXAMPLE 113[4-(4-Chloro-phenyl)-thiazol-5-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amineEXAMPLE 113A (2,4-Dibromo-thiazol-5-yl)-methanol

2,4-Dibromo-thiazole-5-carbaldehyde (2.0 g, 7.4 mmol) in methanol (80mL) was treated with NaBH₄ (419 mg, 11.0 mmol). The reaction mixture wasstirred at rt overnight, quenched with 10% NaOH, diluted with water andextracted with ethyl acetate (2×). The solvent was removed, and theresulting residue was chromatographed using hexane/ethyl acetate (3:1)to give the title compound (1.84 g, 91%). MS (DCI/NH₃) m/z 274 (M)⁺. ¹HNMR (500 MHz, CDCl₃) δ ppm 2.11 (s, 1H) 4.78 (s, 2H).

EXAMPLE 113B2,4-Dibromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiazole

The product from Example 113A following the same procedure as Example76A gave the title compound. MS (DCI/NH₃) m/z 386 (M)⁺, 388 (M+2)⁺. ¹HNMR (400 MHz, CDCl₃) δ ppm 0.11 (s, 6H) 0.92 (s, 9H) 4.74 (s, 2H).

EXAMPLE 113C 4-Bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiazole

The product from Example 113B (1.85 g, 4.78 mmol) in diethyl ether (100mL) was treated with drop wise n-BuLi (2.5 M in tetrahydrofuran) (1.9mL, 4.78 mmol) at −78° C. for 1 hr. The reaction was quenched with H₂O(10 mL), stirred 45 min until reaching rt, diluted with water andextracted with ethyl acetate (2×). The solvent was removed, and theresulting residue was chromatographed using hexane/ethyl acetate (3:1)to give the title compound (970 mg, 66%). MS (DCI/NH₃) m/z 308 (M)⁺, 310(M+2)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.12 (s, 6H) 0.93 (s, 9H) 4.83 (s,2H) 8.68 (s, 1H).

EXAMPLE 113D5-(tert-Butyl-dimethyl-silanyloxymethyl)-4-(4-chloro-phenyl)-thiazole

A flask was charged with the product from Example 113C (300 mg, 0.97mmol), 4-chloro-phenyl-boronic acid (183 mg, 1.17 mmol), Na₂CO₃ (2M)(1.46 mL, 2.91 mmol) and PdCl₂(PPh₃)₂ (34 mg, 0.05 mmol) inDME/H₂O/ethanol (7:3:2) (20 mL). The reaction mixture was heated at 85°C. overnight. After cooling to room temperature, the mixture was dilutedwith ethyl acetate and washed with water, dried (MgSO₄), filtered andconcentrated. The resulting residue was chromatographed usinghexane/ethyl acetate (9:1) to give the title compound (185 mg, 56%). MS(DCI/NH₃) m/z 340 (M)⁺,

¹H NMR (500 MHz, CDCl₃) δ ppm 0.10 (s, 6H) 0.94 (s, 9H) 4.94 (s, 2H)7.43 (d, J=8.24 Hz, 2H) 7.61 (d, J=8.24 Hz, 2H) 8.75 (s, 1H).

EXAMPLE 113E [4-(4-Chloro-phenyl)-thiazol-5-yl]-methanol

The product from Example 113D following the same procedure as Example76D gave the title compound. MS (DCI/NH₃) m/z 226 (M)⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 4.95 (d, J=4.60 Hz, 2H) 7.43 (d, J=8.59 Hz, 2H) 7.64 (d,J=8.59 Hz, 2H) 8.79 (s, 1H).

EXAMPLE 113F 5-Azidomethyl-4-(4-chloro-phenyl)-thiazole

The product from Example 113E following the same procedure as Example77A gave the title compound. MS (DCI/NH₃) m/z 251 (M)⁺.

EXAMPLE 113G C-[4-(4-Chloro-phenyl)-thiazol-5-yl]-methylamine

The product from Example 113F following the same procedure as Example77B gave the title compound. MS (DCI/NH₃) m/z 225 (M)⁺.

EXAMPLE 113H[4-(4-Chloro-phenyl)-thiazol-5-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine

The product from Example 113G was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 437 (M)⁺, 439 (M+2)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.79 (d, J=5.22 Hz, 2H) 7.52 (s, 1H) 7.54(s, 1H) 7.61 (d, J=7.98 Hz, 1H) 7.66 (dd, J=7.98, 1.84 Hz, 1H) 7.71 (s,1H) 7.73 (s, 1H) 7.94 (dd, J=7.98, 1.53 Hz, 1H) 7.97 (t, J=5.22 Hz, 1H)9.04 (s, 1H).

EXAMPLE 1141-(2,3-dichlorophenyl)-N-(quinolin-5-ylmethyl)-1H-tetrazol-5-amine

1-quinolin-5-ylmethanamine (Adachi; Oota; Kanazawa Daigaku YakugakubitKenkyo Nempo; 7; 1957; 10) was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 371 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.97 (d, J=5.42 Hz, 2H) 7.52-7.64 (m, 3H) 7.67-7.76(m, 2H) 7.79 (t, J=5.59 Hz, 1H) 7.92 (dd, J=8.14, 1.70 Hz, 1H) 7.96 (d,J=8.48 Hz, 1H) 8.56 (dq, J=8.65, 0.85 Hz, 1H) 8.92 (dd, J=4.07, 1.70 Hz,1H). Anal. calcd for C₁₇H₁₂Cl₂N₆: C, 55.00; H, 3.26; N, 22.64. Found: C,54.86; H, 2.98; N, 22.63.

EXAMPLE 1151-(2,3-dichlorophenyl)-N-[(2-morpholin-4-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 115A 4-[3-(azidomethyl)pyridin-2-yl]morpholine

To a solution of (2-morpholino-3-pyridinyl)methanol (1 g, 5.01 mmol) indichloromethane (20 ml) was added thionyl chloride (3 ml) dropwise at 0°C. and allowed to warm to room temperature. After stirring at roomtemperature for 6 h, solvents were removed under reduced pressure andthe residue was dissolved and concentrated repeatedly in dichloromethaneto remove excess of thionyl chloride. The obtained crude chlorideintermediate, (2-morpholino-3-pyridinyl)methylchloride, was immediatelydissolved in acetone (25 ml) and added sodium azide (1.63 g, 25.05 mmol)at room temperature. The reaction was refluxed for overnight, solventswere removed under reduced pressure, dissolved in dichloromethane (25ml) and washed with 1M NaHCO₃ (25 ml). The aqueous layer was extractedwith dichloromethane (2×20 ml). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated to yield 0.62 g (57%) of product asa thick yellowish liquid. MS (ESI⁺) m/z 220 (M+H)⁺;

EXAMPLE 115B (2-morpholin-4-ylpyridin-3-yl)methylamine

To a solution of the product from Example 115A (0.62 g) in methanol (10ml) was added Pd/C (0.06 g) under N₂ atmosphere. The reaction mixturewas stirred at room temperature under H₂ atmosphere. After 6 h, thereaction mixture was filtered through celite and concentrated to yield0.42 g (78%) of product. MS (ESI⁺) m/z 194 (M+H)⁺;

EXAMPLE 115C1-(2,3-dichlorophenyl)-N-[(2-morpholin-4-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

The product of Example 115B was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 406 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.88-3.17 (m, 4H) 3.62-3.80 (m, 4H) 4.51 (d, J=5.76Hz, 2H) 7.04 (dd, J=7.46, 4.75 Hz, 1H) 7.60-7.66 (m, 2H) 7.69-7.76 (m,2H) 7.95 (dd, J=8.14, 1.70 Hz, 1H) 8.20 (dd, J=4.92, 1.86 Hz, 1H). Anal.calcd for C₁₇H₁₇Cl₂N₇O: C, 50.26; H, 4.22; N, 24.13. Found: C, 50.50; H,3.92; N, 24.33.

EXAMPLE 1161-[2-fluoro-3-(trifluoromethyl)phenyl]-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amineEXAMPLE 116A 2-fluoro-1-isothiocyanato-3-trifluoromethyl-benzene

To a two phase solution of 2-fluoro-3-trifluoromethyl-phenylamine (2 g,11.17 mmole) in dichloromethane (40 ml) and sodium bicarbonate (6.57 g,78.19 mmole) in water (30 ml) at 0° C. was added dropwise a solution ofthiophosgene (1.28 g, 11.17 mmole) in dichloromethane (10 ml). After 2hrs, the organic layer was separated, washed sequentially with 1MNaHCO₃, brine and water. The organic layer was dried over Na₂SO₄,filtered and concentrated to yield 2.2 g (91%) of product as a viscousliquid. MS (ESI⁺) m/z 221 (M+H)⁺.

EXAMPLE 116B1-[2-fluoro-3-(trifluoromethyl)phenyl]-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

The product from Example 116A was treated with2-(pyridin-2-yloxy)benzylamine hydrochloride according to the method ofExample 78C to provide the title compound. MS (ESI⁺) m/z 431 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 4.44 (d, J=5.76 Hz, 2H) 7.01 (d, J=8.48 Hz,1H) 7.05-7.16 (m, 2H) 7.22 (td, J=7.46, 1.36 Hz, 1H) 7.33 (td, J=7.63,1.70 Hz, 1H) 7.40 (dd, J=7.63, 1.53 Hz, 1H) 7.64 (t, J=7.97 Hz, 1H) 7.76(t, J=5.60 Hz, 1H) 7.81-7.89 (m, 1H) 7.96 (t, J=7.63 Hz, 1H) 8.03-8.13(m, 2H). Anal. calcd for C₂₀H₁₄F₄N₆O: C, 55.82; H, 3.28; N, 19.53.Found: C, 55.60; H, 3.05; N, 19.56.

EXAMPLE 1171-[2-chloro-3-(trifluoromethyl)phenyl]-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

2-chloro-1-isothiocyanato-3-trifluoromethyl-benzene Thiophosgene and2-chloro-3-trifluoromethyl-phenylamine were processed according to themethod of Example 116A to provide the product. MS (ESI⁺) m/z 237 (M+H)⁺.

EXAMPLE 117B1-[2-chloro-3-(trifluoromethyl)phenyl]-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

The product of Example 117A was treated with2-(pyridin-2-yloxy)benzylamine hydrochloride according to the method ofExample 78C to provide the title compound. MS (ESI⁺) m/z 447 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 4.42 (d, J=5.76 Hz, 2H) 7.02 (d, J=8.14 Hz,1H) 7.06-7.15 (m, 2H) 7.21 (td, J=7.38, 1.19 Hz, 1H) 7.32 (td, J=7.71,1.87 Hz, 1H) 7.40 (dd, J=7.46, 1.70 Hz, 1H) 7.63 (t, J=5.76 Hz, 1H)7.75-7.89 (m, 2H) 7.92-7.98 (m, 1H) 8.07-8.18 (m, 2H). Anal. calcd forC₂₀H₁₄ClF₄N₆O: C, 53.76; H, 3.16; N, 18.81. Found: C, 53.74; H, 2.93; N,18.86.

EXAMPLE 1181-(2,3-dichlorophenyl)-N-[2-(pyridin-3-yloxy)benzyl]-1H-tetrazol-5-amine

The compound, 2,3-dichlorophenylisothiocyanate was treated with2-(pyridin-3-yloxy)benzylamine hydrochloride according to the method ofExample 78C to provide the title compound. MS (ESI⁺) m/z 413 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 4.52 (d, J=5.76 Hz, 2H) 6.90-6.96 (m, 1H)7.20 (td, J=7.54, 0.85 Hz, 1H) 7.28-7.48 (m, 4H) 7.55-7.69 (m, 3H) 7.94(dd, J=7.29, 2.54 Hz, 1H) 8.31-8.38 (m, 2H).

EXAMPLE 1191-(2,3-dichlorophenyl)-N-(2-pyridin-3-ylbenzyl)-1H-tetrazol-5-amineEXAMPLE 119A (2-pyridin-3-yl-phenyl)-methanol

To a solution of 2-pyridin-3-yl-benzaldehyde (1 g, 5.46 mmole) inmethanol (10 ml) was added a solution of NaBH₄ (0.26 g, 6.82 mmole) inmethanol (10 ml) at 0° C. and stirred for 30 min at same temperature andthen refluxed for 1 h. The unreacted NaBH₄ was decomposed by solution of6N HCl. The solvent was removed under reduced pressure and the residuewas dissolved in 5N NaOH (20 ml) and extracted with ethyl acetate (3×20ml). Combined organic extracts were dried (Na₂SO₄), filtered andconcentrated to yield 0.95 g (94%) of product. MS (ESI⁺) m/z 186 (M+H)⁺.

EXAMPLE 119B 3-[2-(azidomethyl)phenyl]pyridine

The product of Example 119A, thionyl chloride and sodium azide wereprocessed according to the method of Example 115A to provide theproduct. MS (ESI⁺) m/z 211 (M+H)⁺.

EXAMPLE 119C 1-(2-pyridin-3-ylphenyl)methanamine

The product of Example 119B and Pd/C were processed according to themethod of Example 115B to provide the product. MS (ESI⁺) m/z 185 (M+H)⁺.

EXAMPLE 119D1-(2,3-dichlorophenyl)-N-(2-pyridin-3-ylbenzyl)-1H-tetrazol-5-amine

The product of Example 119C was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 397 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.41 (d, J=5.43 Hz, 2H) 7.25-7.31 (m, 1H) 7.35-7.52(m, 4H) 7.59-7.67 (m, 3H) 7.83-7.88 (m, J=8.14, 2.03, 1.70 Hz, 1H) 7.93(dd, J=7.46, 2.37 Hz, 1H) 8.57-8.63 (m, 2H).

EXAMPLE 1201-(2,3-dichlorophenyl)-N-(2-pyridin-4-ylbenzyl)-1H-tetrazol-5-amineEXAMPLE 120A (2-pyridin-4-ylphenyl)methanol

2-pyridin-4-yl-benzaldehyde was treated with NaBH₄ according to themethod of Example 119A to provide the title compound. MS (ESI⁺) m/z 185(M+H)⁺;

EXAMPLE 120B 4-[2-(azidomethyl)phenyl]pyridine

The product of Example 120A, thionyl chloride and sodium azide wereprocessed according to the method of Example 115A to provide theproduct. MS (ESI⁺) m/z 211 (M+H)⁺.

EXAMPLE 120C 1-(2-pyridin-4-ylphenyl)methanamine

The product of Example 120B and Pd/C were processed according to themethod of Example 115B to provide the product. MS (ESI⁺) m/z 186 (M+H)⁺;

EXAMPLE 120D 1-(2-pyridin-4-ylphenyl)methanamine

The product of Example 120C was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 397 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.43 (d, J=5.42 Hz, 2H) 7.25-7.30 (m, 1H) 7.36-7.52(m, 5H) 7.58-7.67 (m, 3H) 7.94 (dd, J=7.29, 2.54 Hz, 1H) 8.61-8.66 (m,2H).

EXAMPLE 1211-(2,3-dichlorophenyl)-N-[(4-methyl-1,3-thiazol-5-yl)methyl]1H-tetrazol-5-amine

C-(4-methyl-thiazol-5-yl)-methylamine (Buchman; Sargent; J. Amer. Chem.Soc Vol. 67, page 400, 1945) was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 341 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.39 (s, 3H) 4.62 (d, J=5.76 Hz, 2H) 7.56-7.70 (m,2H) 7.76 (t, J=5.76 Hz, 1H) 7.95 (d, J=8.14 Hz, 1H) 8.85 (s, 1H).

EXAMPLE 1221-(2,3-dichlorophenyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

2,3-dichlorophenylisothiocyanate was treated with3-aminomethyl-6-(trifluoromethyl)pyridine according to the method ofExample 78C to provide the title compound. MS (ESI⁺) m/z 389 (M+H)⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.62 (d, J=5.76 Hz, 2H) 7.63 (t, J=7.97 Hz,1H) 7.77 (d, J=9.49 Hz, 1H) 7.82-8.05 (m, 4H) 8.74 (s, 1H).

EXAMPLE 123{1-[2-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)phenyl]piperidin-4-yl}methanol

2,3-dichlorophenylisothiocyanate was treated with[1-[2-(aminomethyl)phenyl]-4-piperidinyl]methanol according to themethod of Example 78C to provide the title compound. MS (ESI⁺) m/z 433(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.33 (m, 2H) 1.47 (br. s.,1H) 1.74 (d, J=11.19 Hz, 2H) 2.61 (t, J=10.85 Hz, 2H) 3.00 (d, J=11.87Hz, 2H) 4.47 (t, J=5.26 Hz, 1H) 4.55 (d, J=5.76 Hz, 2H) 7.02 (t, J=7.46Hz, 1H) 7.11 (d, J=7.12 Hz, 1H) 7.18-7.30 (m, 2H) 7.54 (t, J=5.76 Hz,1H) 7.60 (t, J=7.97 Hz, 1H) 7.68-7.73 (m, 1H) 7.93 (dd, J=8.31, 1.19 Hz,1H).

EXAMPLE 1241-(2,3-dichlorophenyl)-N-[(2-ethylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 124A (2-ethylpyridin-3-yl)methanol

To a suspension of LiAlH₄ (0.83 g, 21.76 mmol) in tetrahydrofuran (50ml) was added drop wise a solution of 2-ethyl-nicotinic acid ethyl ester(Breitmaier et al, Tetrahedron, 26, 1970, 5907-5910) (3 g, 16.74 mmol)in tetrahydrofuran (25 ml) at −50° C. After addition, the temperaturewas slowly allowed to increase to 0° C. After 3 h, the reaction wasquenched with saturated NH₄Cl, filtered and washed with 1M NaHCO₃ (50ml). The aqueous layer was extracted with ethyl acetate (3×50 ml).Combined organic extract were dried (Na₂SO₄), filtered and concentratedto yield 1.6 g (54%) of product as a yellowish liquid. MS (ESI⁺) m/z 138(M+H)⁺;

EXAMPLE 124B 3-(azidomethyl)-2-ethylpyridine

The product of Example 124A, thionyl chloride and sodium azide wereprocessed according to the method of Example 115A to provide theproduct. MS (ESI⁺) m/z 163 (M+H)⁺.

EXAMPLE 124C (2-ethylpyridin-3-yl)methylamine

The product of Example 124B and Pd/C were processed according to themethod of Example 115B to provide the product. MS (ESI⁺) m/z 137 (M+H)⁺.

EXAMPLE 124D1-(2,3-dichlorophenyl)-N-[(2-ethylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

The product of Example 124C was treated with2,3-dichlorophenylisothiocyanate according to the method of product ofExample 78C to provide the title compound. MS (ESI⁺) m/z 349 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.21 (t, J=7.46 Hz, 3H) 2.80 (q, J=7.46 Hz,2H) 4.51 (d, J=5.76 Hz, 2H) 7.19 (dd, J=7.80, 4.75 Hz, 1H) 7.57-7.70 (m,3H) 7.71-7.76 (m, 1H) 7.95 (dd, J=8.14, 1.36 Hz, 1H) 8.39 (dd, J=4.75,1.70 Hz, 1H).

EXAMPLE 1251-(2,3-dichlorophenyl)-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine

2,3-dichlorophenylisothiocyanate was treated with product from Example193C according to the method of product of Example 78C to provide thetitle compound. MS (ESI⁺) m/z 339 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 4.51 (d, J=5.76 Hz, 2H) 7.30-7.39 (m, 1H) 7.62 (t, J=7.97 Hz, 1H)7.71-7.83 (m, 2H) 7.86-7.99 (m, 2H) 8.15 (td, J=3.22, 1.70 Hz, 1H)

EXAMPLE 1261-(2,3-dichlorophenyl)-N-{2-[2-(diethylamino)ethoxy]benzyl}-1H-tetrazol-5-amineEXAMPLE 126A N-{2-[2-(azidomethyl)phenoxy]ethyl}-N,N-diethylamine

[2-(2-diethylamino-ethoxy)-phenyl]methanol (Cossey, H. D. et al.; J.Chem. Soc. 1965; 954-973), thionyl chloride and sodium azide wereprocessed according to the method of Example 115A to provide theproduct. MS (ESI⁺) m/z 249 (M+H)⁺.

EXAMPLE 126B N-{2-[2-(aminomethyl)phenoxy]ethyl}-N,N-diethylamine

The product of Example 126A and Pd/C were processed according to themethod of Example 115B to provide the product. MS (ESI⁺) m/z 223 (M+H)⁺.

EXAMPLE 126C1-(2,3-dichlorophenyl)-N-{2-[2-(diethylamino)ethoxy]benzyl}-1H-tetrazol-5-amine

The product of Example 126B was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 435 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.98 (t, J=7.12 Hz, 6H) 2.50-2.53 (m, 2H) 2.53-2.63(m, 2H) 2.69-2.87 (m, 2H) 3.97-4.10 (m, 2H) 4.46 (d, J=5.76 Hz, 2H) 6.89(t, J=7.80 Hz, 1H) 6.98 (d, J=7.80 Hz, 1H) 7.13-7.30 (m, 2H) 7.46 (t,J=5.59 Hz, 1H) 7.61 (t, J=7.97 Hz, 1H) 7.68-7.78 (m, 1H) 7.94 (dd,J=8.14, 1.70 Hz, 1H).

EXAMPLE 127N-[(2-chloro-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 127A 3-(azidomethyl)-2-chloro-5-fluoropyridine

(2-chloro-5-fluoro-pyridin-3-yl)-methanol, thionyl chloride and sodiumazide were processed according to the method of Example 115A to providethe product. MS (ESI⁺) m/z 187 (M+H)⁺.

EXAMPLE 127B (2-chloro-5-fluoropyridin-3-yl)methylamine

The product of Example 127A was processed according to the method ofExample 115B except that Pt/C was used instead of Pd/C as catalyst. MS(ESI⁺) m/z 161 (M+H)⁺.

EXAMPLE 127CN-[(2-chloro-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The product of Example 127B was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 373 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.54 (d, J=5.76 Hz, 2H) 7.65 (t, J=8.14 Hz, 1H) 7.75(dd, J=8.81, 2.71 Hz, 1H) 7.83 (dd, J=7.97, 1.53 Hz, 2H) 7.97 (dd,J=8.14, 1.36 Hz, 1H) 8.41 (d, J=3.05 Hz, 1H).

EXAMPLE 1281-(2,3-dichlorophenyl)-N-[4-fluoro-3-(pyrazin-2-yloxy)benzyl]-1H-tetrazol-5-amineEXAMPLE 128A ethyl 4-fluoro-3-hydroxybenzoate

To a solution of 4-fluoro-3-hydroxy-benzoic acid (2 g, 12.81 mmol) inabsolute ethanol (30 ml) was added thionyl chloride (1 ml) drop wise at0° C. After refluxing for overnight, the solvents were driven off, theresidue was dissolved in dichloromethane (50 ml), cooled on ice bath,neutralized slowly with 1M NaHCO₃, and the layers were separated. Theaqueous layer was extracted with dichloromethane (50 ml) for one moretime. Combined organic extracts were dried (Na₂SO₄), filtered,concentrated, and purified by flash column chromatography usingdichloromethane to yield 2.2 g (93%) of product. MS (ESI⁺) m/z 185(M+H)⁺.

EXAMPLE 128B ethyl 4-fluoro-3-(pyrazin-2-yloxy)benzoate

To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g,11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH inmineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol)and heated at 80° C. for overnight. One more equivalent ofchloropyrazine was added and heated at the same temperature for 10 h.The reaction mixture was poured into a flask containing 150 ml ofaqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixturewas extracted with ethyl acetate (3×100 ml), the combined organicextracts were washed with sat NaCl (150 ml), dried (Na₂SO₄), filteredand concentrated. The crude product was purified by flash columnchromatography using dichloromethane to yield 1.55 g (50%) of product.MS (ESI⁺) m/z 263 (M+H)⁺;

EXAMPLE 128C [4-fluoro-3-(pyrazin-2-yloxy)phenyl]methanol

The product of Example 128B and LiAlH₄ were processed according to themethod of Example 124B to provide the product. MS (ESI⁺) m/z 221 (M+H)⁺.

EXAMPLE 128D 2-[5-(azidomethyl)-2-fluorophenoxy]pyrazine

The product of Example 128C, thionyl chloride and sodium azide wereprocessed according to the method of Example 115A to provide theproduct. MS (ESI⁺) m/z 237 (M+H)⁺.

EXAMPLE 128E 1-[4-fluoro-3-(pyrazin-2-yloxy)phenyl]methanamine

The product of Example 128B was processed according to the method ofExample 115B except that Pt/C was used instead of Pd/C as catalyst. MS(ESI⁺) m/z 220 (M+H)⁺.

EXAMPLE 128F1-(2,3-dichlorophenyl)-N-[4-fluoro-3-(pyrazin-2-yloxy)benzyl]-1H-tetrazol-5-amine

The product of Example 128E was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 432 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.49 (d, J=5.76 Hz, 2H) 7.23-7.41 (m, 3H) 7.61 (t,J=7.97 Hz, 1H) 7.69-7.78 (m, 2H) 7.95 (dd, J=8.14, 1.36 Hz, 1H) 8.18(dd, J=2.54, 1.53 Hz, 1H) 8.42 (d, J=2.71 Hz, 1H) 8.66 (d, J=1.36 Hz,1H).

EXAMPLE 1291-(2,3-dichlorophenyl)-N-[(3-fluoropyridin-4-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 129A ethyl 3-fluoroisonicotinate

3-fluoro-isonicotinic acid and ethyl alcohol were processed according tothe method of Example 128A to provide the product. MS (ESI⁺) m/z 170(M+H)⁺;

EXAMPLE 129B (3-fluoropyridin-4-yl)methanol

The product of Example 129A and LiAlH₄ were processed according to themethod of Example 124B to provide the product. MS (ESI⁺) m/z 128 (M+H)⁺;

EXAMPLE 129C 4-(azidomethyl)-3-fluoropyridine

The product of Example 129B, thionyl chloride and sodium azide wereprocessed according to the method of Example 115A to provide theproduct. MS (ESI⁺) m/z 153 (M+H)⁺.

EXAMPLE 129D (3-fluoropyridin-4-yl)methylamine

The product of Example 129C was processed according to the method ofExample 115B except that Pt/C was used instead of Pd/C as catalyst. MS(ESI⁺) m/z 127 (M+H)⁺;

EXAMPLE 129E1-(2,3-dichlorophenyl)-N-[(3-fluoropyridin-4-yl)methyl]-1H-tetrazol-5-amine

The product of Example 129D was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 339 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.58 (d, J=5.76 Hz, 2H) 7.39 (dd, J=6.27, 5.26 Hz,1H) 7.64 (t, J=8.14 Hz, 1H) 7.73-7.81 (m, 1H) 7.86 (t, J=5.76 Hz, 1H)7.94-8.00 (m, 1H) 8.40 (dd, J=4.75, 1.02 Hz, 1H) 8.53 (d, J=1.70 Hz,1H).

EXAMPLE 130N-[(3-chloropyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 130A (3-chloropyridin-4-yl)methanol

The title compound was prepared using the procedure as described inMarsais, Francis; Breant, Patrice; Ginguene, Alain; Queguiner, Guy;Organomet. Chem. Vol. 216 page 139-147 1981. MS (ESI⁺) m/z 144 (M+H)⁺.

EXAMPLE 130A 4-(azidomethyl)-3-chloropyridine

3-chloro-pyridin-4-yl)-methanol (Marsais, Francis; Breant, Patrice;Ginguene, Alain; Queguiner, Guy; Organomet. Chem. Vol. 216 page 139-147,1981), thionyl chloride and sodium azide were processed according to themethod of Example 115A to provide the product. MS (ESI⁺) m/z 170 (M+H)⁺.

EXAMPLE 130C (3-chloropyridin-4-yl)methylamine

The product of Example 130B was processed according to the method ofExample 115B except that Pt/C was used instead of Pd/C as catalyst. MS(ESI⁺) m/z 143 (M+H)⁺;

EXAMPLE 130DN-[(3-chloropyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The product of Example 130C was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 355 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.58 (d, J=5.76 Hz, 2H) 7.37 (d, J=5.09 Hz, 1H) 7.65(t, J=8.14 Hz, 1H) 7.78-7.83 (m, 1H) 7.90 (t, J=5.76 Hz, 1H) 7.98 (dd,J=8.14, 1.70 Hz, 1H) 8.50 (d, J=5.09 Hz, 1H) 8.61 (s, 1H).

EXAMPLE 1311-(2,3-dichlorophenyl)-N-[1-(2-methylpyridin-3-yl)ethyl]-1H-tetrazol-5-amineEXAMPLE 131A 1-(2-methylpyridin-3-yl)ethanone

To a solution of 1-(2-methyl-pyridin-3-yl)-ethanone (Schmelkes; Joiner;J. Amer. Chem. Soc.; 61; 1939; 2562) (0.8 g, 6 mmol) in absolute ethanol(10 ml) was added HCl salt of methoxylamine (0.5 g, 6 mmol) and stirred60° C. for overnight. To drive the reaction to the completion, 0.5equivalent more of methoxylamine chloride was added and heated at thesame temperature for 6 h. Solvents were driven off and the residue wasdissolved in ethyl acetate and washed with 1M NaHCO₃. The solution wasdried (Na₂SO₄) and concentrated to yield 0.66 (67%) g of product. MS(ESI⁺) m/z 165 (M+H)⁺.

EXAMPLE 131C 1-(2-methylpyridin-3-yl)ethanamine

To a solution of the product of Example 131B (0.61 g, 3.72 mmol) in 7NNH₃ in methanol (50 ml) was added Raney nickel (6.1 g) under argonatmosphere. The reaction mixture was kept on shaker under 60 psi H₂atmosphere. After 6 h at room temperature, the reaction mixture wasfiltered through micro pore filter and concentrated to yield 0.45 g(88%) of product. MS (ESI⁺) m/z 137 (M+H)⁺.

EXAMPLE 131D1-(2,3-dichlorophenyl)-N-[1-(2-methylpyridin-3-yl)ethyl]-1H-tetrazol-5-amine

The product of Example 131C was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 349 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.43 (d, J=6.78 Hz, 3H) 2.58 (s, 3H) 4.93-5.13 (m,1H) 7.19 (dd, J=7.63, 4.92 Hz, 1H) 7.52-7.77 (m, 4H) 7.97 (dd, J=7.97,1.86 Hz, 1H) 8.30 (dd, J=4.75, 1.70 Hz, 1H).

EXAMPLE 1321-(2,3-dichlorophenyl)-N-[(2,2-difluoro-1,3-benzodioxol-4-yl)methyl]-1H-tetrazol-5-amine

C-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-methylamine (Schlosser et al.Eur. J. Org. Chem. Vol. 3, page 452-462, 2003) was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 400 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.56 (d, J=5.76 Hz, 2H) 7.16-7.19 (m, 2H) 7.29-7.34(m, 1H) 7.58-7.65 (m, 1H) 7.68-7.74 (m, 1H) 7.84 (t, J=5.76 Hz, 1H) 7.96(dd, J=8.14, 1.70 Hz, 1H).

EXAMPLE 1331-[2-fluoro-3-(trifluoromethyl)phenyl]-N-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The C-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-methylamine was treatedwith 2,3-dichlorophenylisothiocyanate according to the method of Example78C to provide the title compound. MS (ESI⁺) m/z 437 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.49 (d, J=5.42 Hz, 2H) 5.03 (q, J=9.04 Hz, 2H) 7.11(dd, J=7.29, 4.92 Hz, 1H) 7.61-7.73 (m, 2H) 7.83 (t, J=5.76 Hz, 1H)8.03-8.14 (m, 3H).

EXAMPLE 1341-(2,3-dichlorophenyl)-N-{[2-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]methyl}1H-tetrazol-5-amineEXAMPLE 134A 2-(2,6-dimethylmorpholin-4-yl)nicotinonitrile

A solution of 2-fluoro-nicotinonitrile (1.06 g, 8.69 mmol) and2,6-dimethyl-morpholine (1.0 g, 8.69 mmol) in tetrahydrofuran (10 ml)was heated at 110° C. for 10 min in a microwave reactor. The reactionmixture was concentrated and purified by flash column chromatographyusing hexanes:ethylacetate (2:1) to yield 0.37 g (40%) of product. MS(ESI⁺) m/z 218 (M+H)⁺;

EXAMPLE 134B [2-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]methylamine

The product of Example 134A and Raney/nickel were processed according tothe method of Example 13° C. to provide the product. MS (ESI⁺) m/z 222(M+H)⁺;

EXAMPLE 134C1-(2,3-dichlorophenyl)-N-{[2-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The product of Example 134B was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 434 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.10 (d, J=6.44 Hz, 6H) 2.44 (d, J=10.17 Hz, 2H)3.20 (d, J=11.87 Hz, 2H) 3.65-3.82 (m, 2H) 4.50 (d, J=5.42 Hz, 2H) 7.02(dd, J=7.63, 4.92 Hz, 1H) 7.56-7.75 (m, 4H) 7.94 (dd, J=7.97, 1.53 Hz,1H) 8.18 (dd, J=4.75, 2.03 Hz, 1H).

EXAMPLE 1351-(2,3-dichlorophenyl)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-1H-tetrazol-5-amineEXAMPLE 135A 6-fluoroindan-1-one O-methyloxime

To a solution of 6-fluoro-indan-1-one (0.5 g, 3.33 mmol) in pyridine (10ml) was added the HCl salt of methoxylamine (0.31 g, 3.66 mmol) andstirred at room temperature for overnight. The reaction mixture wasdiluted with ethylacetate (50 ml), acidified with 3N HCl, and washedwith 1N HCl, water and brine sequentially. The solution was dried(Na₂SO₄) and concentrated to yield 0.48 g (81%) of product. MS (ESI⁺)m/z 180 (M+H)⁺;

EXAMPLE 135B 6-fluoro-2,3-dihydro-1H-inden-1-ylamine

The product of Example 135A and Raney/nickel were processed according tothe method of Example 131C to provide the product. MS (ESI⁺) m/z 152(M+H)⁺;

EXAMPLE 135C1-(2,3-dichlorophenyl)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-1H-tetrazol-5-amine

The product of Example 135B was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 364 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.85-2.09 (m, 1H) 2.51-2.62 (m, 1H) 2.68-3.01 (m,2H) 5.33 (q, J=7.91 Hz, 1H) 6.98-7.11 (m, 2H) 7.27 (dd, J=8.48, 5.09 Hz,1H) 7.53-7.63 (m, 2H) 7.74 (dd, J=7.97, 1.53 Hz, 1H) 7.92 (dd, J=8.14,1.36 Hz, 1H).

EXAMPLE 136N-[4,5-difluoro-2-(pyridin-2-yloxy)benzyl]-1-[2-fluoro-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-amineEXAMPLE 136A 2-(2-bromo-4,5-difluorophenoxy)pyridine

To a solution of 2-bromo-4,5-difluoro-phenol (1 g, 4.78 mmol) inN,N-dimethylformamide were added K₂CO₃ and 2-fluoropyridine (0.46 g,4.78 mmol) and heated at 120° C. for overnight. One more equivalent of2-fluoropyridine was added and heated at 150° C. for 12 h. The reactionmixture was dissolved in ethyl acetate, washed with 1M NaHCO₃,concentrated and purified by flash column chromatography using 0%, 5%and 10% of ethyl acetate in hexanes to yield 0.8 g (59%) of product. MS(ESI⁺) m/z 286 (M+H)⁺.

EXAMPLE 136B 4,5-difluoro-2-(pyridin-2-yloxy)benzonitrile

To a solution of product of Example 136A (0.8 g, 2.76 mmol) inN,N-dimethylformamide (10 ml) were added Zn(CN)₂ (0.18 g, 1.52 mmol) andPd(Ph₃)₄ (0.32 g, 0.28 mmol) and stirred at 120° C. for overnight. Thecrude product was purified by flash column chromatography using 0%, 5%and 10% of ethylacetate in hexanes to yield 0.28 g (44%) of product. MS(ESI⁺) m/z 233 (M+H)⁺;

EXAMPLE 136C 1-[4,5-difluoro-2-(pyridin-2-yloxy)phenyl]methanamine

The product of Example 136B and Raney/nickel were processed according tothe method of Example 131C to provide the product. MS (ESI⁺) m/z 237(M+H)⁺;

EXAMPLE 136DN-[4,5-difluoro-2-(pyridin-2-yloxy)benzyl]-1-[2-fluoro-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-amine

The product of Example 136C was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI⁺) m/z 467 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 4.38 (d, J=5.76 Hz, 2H) 7.04-7.10 (m, 1H) 7.12-7.19(m, 1H) 7.33-7.51 (m, 2H) 7.65 (t, J=7.97 Hz, 1H) 7.78 (t, J=5.59 Hz,1H) 7.83-7.93 (m, 1H) 7.94-8.10 (m, 2H) 8.10-8.14 (m, 1H).

EXAMPLE 137N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-2,3-dihydrospiro[indene-1,4′-piperidin]-3-amineEXAMPLE 137A tert-butyl(3Z)-3-(methoxyimino)-2,3-dihydro-1′H-spiro[indene-1,4′-piperidine]-1′-carboxylate

N-boc-1-[4-spiro-piperidine]-3-indanone and the HCl salt ofmethoxylamine were processed according to the method of Example 135A toprovide the product. MS (ESI⁺) m/z 331 (M+H)⁺.

EXAMPLE 137B tert-butyl3-amino-2,3-dihydro-1′H-spiro[indene-1,4′-piperidine]-1′-carboxylate

The product of Example 137A and Raney/nickel were processed according tothe method of Example 131C to provide the product. MS (ESI⁺) m/z 303(M+H)⁺.

EXAMPLE 137C tert-butyl3-{[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}-2,3-dihydro-1′H-spiro[indene-1,4′-piperidine]-1′-carboxylate

The product of Example 137B was treated with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the product. MS (ESI⁺) m/z 515 (M+H)⁺.

EXAMPLE 137DN-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-2,3-dihydrospiro[indene-1,4′-piperidin]-3-amine

The product of Example 136C (0.2 g, 0.38 mmole) was treated withice-cold trifluoroacetic acid (10 ml) in an ice bath, stirred for 10 minat the same temperature and then for 20 min at room temperature. Theproduct was purified by preparative HPLC on a waters Symmetry C8 column(40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100%acetonitrile:ammonium acetate (10 mM) over 15 min at a flow rate of 70mL/min to yield 0.02 g (13%) of product. MS (ESI⁺) m/z 415 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.32-1.56 (m, 4H) 1.63-1.78 (m, 1H)1.91-2.10 (m, 1H) 2.53-2.68 (m, 1H) 2.68-2.83 (m, 2H) 2.94 (q, 2H) 5.38(q, J=8.14 Hz, 1H) 7.16-7.34 (m, 3H) 7.51-7.62 (m, 2H) 7.69-7.74 (m, 1H)7.91 (dd, J=8.14, 1.36 Hz, 1H).

EXAMPLE 138N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-1′-methyl-2,3-dihydrospiro[indene-1,4′-piperidin]-3-amineEXAMPLE 138A spiro[indene-1,4′-piperidin]-3(2H)-one

N-boc-1-[4-spiro-piperidine]-3-indanone and trifluoroacetic acid wereprocessed according to the method of Example 137D to provide theproduct. No purification was required. MS (ESI⁺) m/z 202 (M+H)⁺.

EXAMPLE 138B 1′-methylspiro[indene-1,4′-piperidin]-3(2H)-one

To the product of Example 138A were added formic acid (88% sol, 0.64 g)and formaldehyde (36% sol, 0.45 g) and stirred at 120° C. overnight. Thecrude product was used in the next step.

EXAMPLE 138C 1′-methylspiro[indene-1,4′-piperidin]-3(2H)-oneO-methyloxime

The product of Example 138B and the HCl salt of methoxylamine wereprocessed according to the method of Example 135A to provide theproduct. MS (ESI⁺) m/z 245 (M+H)⁺.

EXAMPLE 138D 1′-methyl-2,3-dihydrospiro[indene-1,4′-piperidin]-3-amine

The product of Example 138C and Raney/nickel were processed according tothe method of Example 131C to provide the product. MS (ESI⁺) m/z 217(M+H)⁺.

EXAMPLE 138EN-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-1′-methyl-2,3-dihydrospiro[indene-1,4′-piperidin]-3-amine

The Example 138D was treated with 2,3-dichlorophenylisothiocyanateaccording to the method of Example 78C to provide the title compound. MS(ESI⁺) m/z 429 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.34-1.50 (m, 2H)1.54-1.74 (m, 2H) 1.92-2.18 (m, 3H) 2.19 (s, 3H) 2.58-2.80 (m, 3H) 5.37(q, J=8.25 Hz, 1H) 7.12-7.38 (m, 3H) 7.48-7.64 (m, 2H) 7.71 (dd, J=7.97,1.19 Hz, 1H) 7.91 (dd, J=7.97, 1.19 Hz, 1H).

EXAMPLE 1391-(2,3-dichloro-4-fluorophenyl)-N-{[2-(pyridin-3-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 139A 2-(pyridin-3-yloxy)nicotinonitrile

Pyridin-3-ol was treated with 2-chloronicotinonitrile and processedaccording to the method of Example 128B to provide the product. MS(ESI⁺) m/z 198 (M+H)⁺.

EXAMPLE 139B [2-(pyridin-3-yloxy)pyridin-3-yl]methylamine

The product of Example 139A and Raney/nickel were processed according tothe method of Example 131C to provide the product. MS (ESI⁺) m/z 202(M+H)⁺;

EXAMPLE 139C1-(2,3-dichloro-4-fluorophenyl)-N-{[2-(pyridin-3-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The product of Example 139B was treated with the product of Example 192Daccording to the method of Example 78C to provide the title compound. MS(ESI⁺) m/z 432 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.62 (d, J=5.49Hz, 2H) 7.16 (dd, J=7.32, 4.88 Hz, 1H) 7.48 (dd, J=8.09, 4.42 Hz, 1H)7.62 (dq, J=8.24, 1.53, 1.37 Hz, 1H) 7.71-7.78 (m, 2H) 7.81 (dd, J=7.32,1.83 Hz, 1H) 7.89 (dd, J=9.00, 5.34 Hz, 1H) 8.02 (dd, J=4.88, 1.83 Hz,1H) 8.35-8.48 (m, 2H).

EXAMPLE 1401-(2,3-dichloro-4-fluorophenyl)-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine

The product of Example 192D was treated with2-(pyridin-2-yloxy)benzylamine hydrochloride according to the method ofExample 78C to provide the title compound. MS (ESI⁺) m/z 431 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 4.41 (d, J=5.80 Hz, 2H) 7.01 (d, J=8.24 Hz,1H) 7.08 (dd, J=7.93, 0.92 Hz, 1H) 7.12 (qd, 1H) 7.21 (td, J=7.55, 1.07Hz, 1H) 7.32 (td, J=7.78, 1.53 Hz, 1H) 7.40 (dd, J=7.48, 1.37 Hz, 1H)7.54 (t, J=5.80 Hz, 1H) 7.67-7.79 (m, 2H) 7.82-7.91 (m, 1H) 8.06-8.20(m, 1H).

EXAMPLE 141N-[(2-chloropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 141A (2-chloropyridin-3-yl)methylamine hydrochloride

To an oven-dried, N₂-purged, 250-mL, round-bottomed flask containing amagnetic stir bar were added 2-chloro-3-methylpyridine (1.07 mL, 1.28 g,10.0 mmol), N-bromosuccinimide (1.96 g, 11.0 mmol), and carbontetrachloride (50 mL). A reflux condenser with N₂-inlet was attached anda heating mantle was applied. The pale yellow slurry was heated toreflux and stirred for 16 h. After cooling to room temperature, thesolids were removed by vacuum filtration through a glass frit. Themother liquor was concentrated by rotary evaporator to one-half theoriginal volume and the solids again were removed by vacuum filtration.The liquor was concentrated to a golden oil and used for the next stepwithout further purification.

To an oven-dried, N₂-purged, 250-mL, round-bottomed flask containing amagnetic stir bar were added the crude 3-bromomethyl-2-chloropyridinefrom above, hexamethylenetetraazene (1.54 g, 11.0 mmol), and chloroform(30 mL). A reflux condenser with N₂-inlet was attached and a heatingmantle was applied. The pale yellow solution was heated to reflux andstirred for 4 hours. A white precipitate formed after 5 minutes atreflux. After cooling to room temperature, the white solid was collectedby vacuum filtration on a glass frit. The solid was washed with hexanesand dried under house vacuum to give 2.50 g of a fine white powder. Thecrude product was used for the next step without further purification.

To a 100-mL, round-bottomed flask containing a magnetic stir bar wereadded the crude solid product from above, 97% ethanol (15 mL), andconcentrated hydrochloric acid (3.5 mL). A reflux condenser was attachedand a heating mantle was applied. The mixture was heated to reflux andstirred for 16 hours. After 1 hour at reflux, the precipitate dissolvedto form a yellow solution. Gradually, a crystalline precipitate reformedin the reaction. After cooling to room temperature, the solids wereremoved by vacuum filtration on a glass frit. The mother liquor wasconcentrated to one-half the original volume and the solids were againremoved by vacuum filtration. The product was crystallized from thegolden liquor by dropwise addition of anhydrous ether. The fine whitepowder was collected by vacuum filtration on a glass frit, washed withhexanes, and dried under vacuum to give 649 mg (42%) of the titlecompound—as the hydrochloride salt. MS (ESI+) m/z 143.0 (M−35)⁺; ¹H NMR(DMSO-d₆) δ 4.14 (q, J=5.8 Hz, 3H), 7.54 (dd, J=7.6, 4.9 Hz, 1H), 8.12(dd, J=7.8, 1.7 Hz, 1H), 8.43 (dd, J=4.9, 1.9 Hz, 1H), 8.75 (br s, 3H).

EXAMPLE 141BN-[(2-chloropyridin-3-yl)methyl]-N′-(2,3-dichlorophenyl)thiourea

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar were added the product of Example 141A, anhydroustetrahydrofuran (5 mL), and diisopropylethylamine (646 mg, 0.886 mL,5.00 mmol). The flask was sealed with a septum and neatdichlorophenylisothiocyanate (306 mg, 0.213 mL, 1.50 mmol) was added viasyringe. The reaction mixture was stirred at room temperature overnight.Water (10 mL) was added, and the reaction was transferred to aseparatory funnel. The mixture was extracted with dichloromethane (3×10mL). The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated by rotary evaporator to give a brown solid.The product was recrystallized from ethyl acetate/hexanes to give 197 mg(47%) of the title compound as a white powder. MS (ESI⁻) m/z 345.9(M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.75 (d, J=5.1 Hz, 2H), 7.37 (dd, J=8.0, 8.0Hz, 1H), 7.46 (dd, J=7.5, 4.7 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.61 (d,J=7.8 Hz, 1H), 7.76 (dd, J=7.6, 1.5 Hz, 1H), 8.32 (dd, J=4.7, 1.7 Hz,1H), 8.44 (br s, 1H), 9.68 (br s, 1H).

EXAMPLE 141CN-[(2-chloropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar was added the product of Example 141B. The flask wassealed with a septum. Anhydrous tetrahydrofuran (3 mL), neattriethylamine (75.8 mg, 105 μL, 0.75 mmol), and azidotrimethylsilane(28.8 mg, 32.9 mL, 0.250 mmol) were added via syringe. Solid mercury(II)chloride (59.7 mg, 0.220 mmol) was added, and a white precipitate formedimmediately. The mixture was stirred at room temperature for 4 hours.Ethyl acetate (10 mL) was added and the solids were removed by vacuumfiltration through a glass frit. The liquor was washed with water (10mL). The organic phase was dried over magnesium sulfate, filtered, andconcentrated by rotary evaporator to give a white solid. The product wasrecrystallized from ethyl acetate/hexanes to give 23.9 mg (34%) of thetitle compound as a white powder. MS (ESI+) m/z 355.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 5.75 (s, 2H), 7.44 (dd, J=7.5, 4.7 Hz, 1H), 7.64 (dd, J=8.1,8.0 Hz, 1H), 7.76-7.85 (m, 3H), 7.97 (dd, J=8.1, 1.7 Hz, 1H), 8.33 (dd,J=4.7, 1.7 Hz, 1H).

EXAMPLE 142N-[(2-bromopyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 142A (2-bromopyridin-3-yl)methylamine hydrochloride

Prepared in 33% yield from 2-bromo-3-methylpyridine according to theprocedure described for Example 141A. MS (ESI+) m/z 188.8 (M−35)⁺; ¹HNMR (DMSO-d₆) δ4.13 (q, J=5.8 Hz, 2H), 7.57 (dd, J=7.5, 4.7 Hz, 1H),8.05 (dd, J=7.6, 1.9 Hz, 1H), 8.40 (dd, J=4.7, 2.0 Hz, 1H), 8.68 (br s,3H).

EXAMPLE 142BN-[(2-bromopyridin-3-yl)methyl]-N′-(2,3-dichlorophenyl)thiourea

Prepared in 55% yield by treatment of the product of Example 142A with2,3-dichlorophenylisothiocyanate according to the procedure describedfor Example 141B. MS (ESI⁻) m/z 389.9 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.71(d, J=4.4 Hz, 2H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.48 (dd, J=7.5, 4.7Hz, 1H), 7.55 (dd, J=8.1, 1.7 Hz, 1H), 7.58-7.63 (m, 1H), 7.69 (dd,J=7.6, 1.9 Hz, 1H), 8.29 (dd, J=4.7, 2.0 Hz, 1H), 8.44 (br s, 1H), 9.70(br s, 1H).

EXAMPLE 142CN-[(2-bromopyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 34% yield by treatment of Example 142B with mercury(II)chloride and trimethylsilyl azide according to the procedure describedfor Example 141C. MS (ESI+) m/z 400.8 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.50(d, J=5.8 Hz, 2H), 7.46 (dd, J=7.6, 4.6 Hz, 1H), 7.64 (dd, J=8.1, 8.0Hz, 1H), 7.73-7.80 (m, 2H), 7.83 (dd, J=5.8, 5.8 Hz, 1H), 7.97 (dd,J=8.1, 1.4 Hz, 1H), 8.31 (4.7, 1.7 Hz, 1H).

EXAMPLE 1431-(2,3-dichlorophenyl)-N-[(2-fluoropyridin-4-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 143A (2-fluoropyridin-4-yl)methylamine hydrochloride

Prepared in 50% yield from 2-fluoro-4-methylpyridine according to theprocedure described for Example 141A.

EXAMPLE 143B1-(2,3-dichloro-phenyl)-3-(2-fluoro-pyridin-4-ylmethyl)-thiourea

Prepared in 53% yield from the product of Example 143A and2,3-dichlorophenylisothiocyanate according to the procedure describedfor Example 141B. MS (ESI+) m/z 329.9 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.79(d, J=5.8 Hz, 2H), 7.02 (br s, 1H), 7.26 (d, J=5.1 Hz, 1H), 7.39 (d,J=8.1 Hz, 1H), 7.48-7.61 (m, 2H), 8.18 (d, J=5.1 Hz, 1H), 8.43 (br s,1H), 9.69 (br s, 1H).

EXAMPLE 143C1-(2,3-dichlorophenyl)-N-[(2-fluoropyridin-4-yl)methyl]-1H-tetrazol-5-amine

Prepared in 26% yield from the product of Example 143B according to theprocedure described for Example 141C. MS (ESI+) m/z 338.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.57 (d, J=5.8 Hz, 2H), 7.08 (br s, 1H), 7.27-7.31 (m, 1H),7.65 (dd, J=8.1, 8.0 Hz, 1H), 7.81 (dd, J=8.1, 1.7 Hz, 1H), 7.85 (dd,J=6.0, 5.9 Hz, 1H), 7.98 (dd, J=8.1, 1.7 Hz, 1H), 8.19 (d, J=5.1 Hz,1H).

EXAMPLE 144N-[(2-bromopyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 144A C-(2-bromo-pyridin-4-yl)-methylamine hydrochloride

Prepared in 40% yield from 2-bromo-4-methylpyridine according to theprocedure described for Example 141A. MS (ESI+) m/z 186.9 (M−35)⁺; ¹HNMR (DMSO-d₆) δ 4.09 (q, J=6.0 Hz, 2H), 7.58 (dd, J=5.1, 1.4 Hz, 1H),7.84 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.71 (br s, 3H).

EXAMPLE 144BN-[(2-bromopyridin-4-yl)methyl]-N′-(2,3-dichlorophenyl)thiourea

Prepared in 84% yield from the product of Example 144A and2,3-dichlorophenylisothiocyanate according to the procedure describedfor Example 141B and 141C.

MS (ESI+) m/z 391.7 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.79 (d, J=5.8 Hz, 2H),7.02 (br s, 1H), 7.26 (d, J=5.1 Hz, 1H).

EXAMPLE 1451-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amine

To an oven-dried N₂-purged, 20-mL scintillation vial containing amagnetic stir bar was added the product of Example 143C (34 mg, 0.10mmol) and anhydrous tetrahydrofuran (1 mL). Neat pyrrolidine (160 mL,140 mg, 2.0 mmol) was added via syringe, and the vial was sealed. Thereaction mixture was heated to 60° C. and the vial was shaken for 48hours. After cooling to room temperature, the solvent/volatiles wereremoved by rotary evaporator to give a brown oil. The product waspurified by flash chromatography (silica gel: 25% ethyl acetate, 75%hexanes—product R_(f)˜0.2) to give 5.6 mg (14%) of the title compound asa white powder. MS (ESI+) m/z 390.1 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.54 (brs, 4H), 3.46 (br s, 4H), 4.61 (d, J=6.1 Hz, 2H), 6.37 (br s, 1H),6.46-6.48 (m, 1H), 7.39-7.47 (m, 2H), 7.72 (dd, J=7.6, 2.2 Hz, 1H), 8.08(d, J=5.1 Hz, J=5.1 Hz, 1H).

EXAMPLE 1461-(2,3-dichlorophenyl)-N-[(2-phenylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

To a 100-mL, round-bottomed flask containing a magnetic stir bar wereadded Example 142C (800 mg, 2.00 mmol), phenylboronic acid (305 mg, 2.50mmol), and dichlorobis(triphenylphosphine)palladium(II) (140 mg, 0.20mol). Isopropyl alcohol (10 mL) and 2M sodium carbonate solution (10 mL)were added. The flask was stoppered and immersed in an oil bath. Themixture was heated to 50-60° C. and stirred for 8 hours during which ablack emulsion formed. After cooling to room temperature, the mixturewas transferred to a separatory funnel and extracted with ethyl acetate(3×25 mL). The combined organic extracts were dried over magnesiumsulfate, filtered, and concentrated by rotary evaporator to a brown oil.The product was purified by flash chromatography (silica gel: 75% ethylacetate, 25% hexanes—product R_(f)˜0.2) to give 58.3 mg (7%) of thetitle compound as a white powder. MS (ESI+) m/z 396.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.52 (d, J=5.4 Hz, 2H), 7.39 (dd, J=8.0, 4.6 Hz, 1H),7.44-7.51 (m, 3H), 7.56-7.73 (m, 5H), 7.84 (dd, J=7.8, 1.7 Hz, 1H), 7.94(dd, J=7.8, 1.7 Hz, 1H), 8.56 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1471-(2,3-dichlorophenyl)-N-{[2-(4-ethoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 6% yield from(2-bromo-pyridin-3-ylmethyl)-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-aminefrom Example 142C and 4-ethoxyphenylboronic acid according to theprocedure described for Example 146. MS (ESI+) m/z 441.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.36 (t, J=6.9 Hz, 3H), 4.09 (q, J=6.9 Hz, 2H), 4.53 (d,J=5.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.34 (dd, J=7.8, 4.7 Hz, 1H),7.51 (d, J=8.8 Hz, 2H), 7.61 (dd, J=8.1, 8.0 Hz, 1H), 7.67-7.74 (m, 2H),7.81 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (dd, J=8.1, 1.7 Hz, 1H), 8.53 (dd,J=4.6, 1.5 Hz, 1H).

EXAMPLE 1481-(2,3-dichlorophenyl)-N-{[2-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 9% yield from Example 142C and 4-fluorophenylboronic acidaccording to the procedure described for Example 146. MS (ESI+) m/z414.9 (M+H)⁺;

¹H NMR (DMSO-d₆) δ 4.51 (d, J=5.8 Hz, 2H), 7.28-7.34 (m, 2H), 7.40 (dd,J=7.8, 4.7 Hz, 1H), 7.58-7.73 (m, 5H), 7.85 (dd, J=7.8, 1.4 Hz, 1H),7.94 (dd, J=8.1, 1.7 Hz, 1H), 8.55 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1491-(2,3-dichlorophenyl)-N-{[2-(4-methylphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 13% yield from Example 142C and 4-methylphenylboronic acidaccording to the procedure described for Example 146. MS (ESI+) m/z411.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.38 (s, 3H), 4.51 (d, J=5.4 Hz, 2H),7.28 (d, J=7.8 Hz, 2H), 7.36 (dd, J=7.8, 4.7 Hz, 1H), 7.46 (d, J=8.1 Hz,2H), 7.60 (dd, J=8.1, 8.0 Hz, 1H), 7.67-7.72 (m, 2H), 7.82 (dd, J=7.8,1.7 Hz, 1H), 7.94 (dd, J=7.8, 1.7 Hz, 1H), 8.54 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 150N-{[2-(4-chlorophenyl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 31% yield from Example 142C and 4-chlorophenylboronic acidaccording to the procedure described for Example 146. MS (ESI+) m/z430.3 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.51 (d, J=5.4 Hz, 2H), 7.41 (dd,J=7.8, 4.7 Hz, 1H), 7.52-7.73 (m, 7H), 7.86 (dd, J=8.0, 1.5 Hz, 1H),7.94 (dd, J=7.8, 1.7 Hz, 1H), 8.57 (dd, J=4.6, 1.5 Hz, 1H).

EXAMPLE 151N-{[2-(3-chlorophenyl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 23% yield from Example 142C and 3-chlorophenylboronic acidaccording to the procedure described for Example 146. MS (ESI+) m/z432.9 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.52 (d, J=5.5 Hz, 2H), 7.43 (dd,J=8.0, 4.9 Hz, 1H), 7.52-7.67 (m, 7H), 7.87 (dd, J=8.0, 1.5 Hz, 1H),7.94 (dd, J=8.0, 1.9 Hz, 1H), 8.57 (dd, J=4.6, 1.5 Hz, 1H).

EXAMPLE 1521-(2,3-dichlorophenyl)-N-{[2-(3-methylphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 38% yield from Example 142C and 3-methylphenylboronic acidaccording to the procedure described for Example 146. MS (LC-MS, ESI+)m/z 410.8 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.37 (s, 3H), 4.52 (J=5.4 Hz, 2H),7.24-7.27 (m, 1H), 7.35-7.40 (m, 4H), 7.60 (dd, J=8.1, 8.0 Hz, 1H),7.65-7.70 (m, 2H), 7.83 (dd, J=8.0, 1.5 Hz, 1H), 7.94 (dd, J=7.8, 1.7Hz, 1H), 8.55 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1531-(2,3-dichlorophenyl)-N-{[2-(2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 153A 2-(2-methoxy-phenyl)nicotinonitrile

To a 250-mL, round-bottomed flask containing a large magnetic stir barwere added 2-chloro-3-cyanopyridine (1.39 g, 10.0 mmol),2-methoxyphenylboronic acid (1.82 g, 12.0 mmol), anddichlorobis(triphenylphosphine)palladium(II) (351 mg, 0.50 mmol).Isopropyl alcohol (50 mL) and 2M sodium carbonate solution (50 mL) wereadded. The flask was stoppered and immersed in an oil bath heated to80-90° C. The biphasic mixture was stirred vigorously and heated for 8hours. After cooling to room temperature, ethyl acetate (50 mL) wasadded and the black mixture was transferred to a separatory funnel. Theaqueous layer was removed and subsequently extracted with ethyl acetate(3×20 mL). The combined ethyl acetate layers were dried over magnesiumsulfate, filtered, and concentrated by rotary evaporator to give a brownoil. The product was crystallized from ethyl acetate/hexanes to give1.38 g (66%) of the title compound as a tan powder.

EXAMPLE 153B1-(2,3-dichloro-phenyl)-3-[2-(2-methoxy-phenyl)-pyridin-3-ylmethyl]-thiourea

To an argon-purged, thick-walled pressure vessel was added wet Raneynickel (˜5 g). A solution of ammonia-saturated methanol (100 mL) wasadded. The product of Example 153A (1.05 g, 5.00 mmol) was added as asolid. The vessel was inserted into a Parr shaker and was charged with60 psi of H₂ gas. The mixture was shaken at room temperature understatic H₂ pressure for 2 hours. The H₂ gas was vented and the vessel waspurged with argon. The solids were removed by vacuum filtration througha glass frit covered with a nylon filter. The solvent/volatiles wereremoved by rotary evaporator to give a pale green oil that was usedwithout further purification.

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar was added the crudeC-[2-(2-methoxy-phenyl)-pyridin-3-yl]-methylamine (430 mg, 2.0 mmol)from above. The flask was sealed with a septum and purged with N₂atmosphere. Anhydrous tetrahydrofuran (10 mL) was added via syringe.Neat 2,3-dichlorophenylisothiocyanate (510 mg, 356 μL, 2.50 mmol) wasadded via syringe. The pale green solution was stirred at roomtemperature overnight. Saturated aqueous sodium bicarbonate (10 mL) wasadded to quench. The mixture was transferred to a separatory funnel andextracted with dichloromethane (3×10 mL). The combined organic extractswere dried over magnesium sulfate, filtered, and concentrated by rotaryevaporator to give a tan solid. The product was recrystallized fromethyl acetate/hexanes to give a 712 mg (85%) of the title compound as awhite powder. MS (LC-MS, ESI+) m/z 417.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 3.74(s, 3H), 4.35 (br s, 1H), 4.66 (br s, 1H), 7.03-7.13 (m, 2H), 7.22 (dd,J=7.5, 1.7 Hz, 1H), 7.31-7.60 (m, 6H), 7.74 (dd, J=7.1, 1.0 Hz, 1H),8.23 (br s, 1H), 8.51 (dd, J=4.9, 1.5 Hz, 1H), 9.46 (br s, 1H).

EXAMPLE 153C1-(2,3-dichlorophenyl)-N-{[2-(2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

To an oven-dried, 100-mL, round-bottomed flask containing a magneticstir bar were added the product of Example 153B (628 mg, 1.50 mmol),sodium azide (293 mg, 4.50 mmol), and anhydrous tetrahydrofuran (15 mL).Neat triethylamine (455 mg, 627 μL, 4.50 mmol) was added via syringe.Solid mercury(II) chloride (448 mg, 1.65 mmol) was added in one portion.A thick, white precipitate formed upon addition of the mercury salt. Themixture was stirred at room temperature overnight during which thesolids darkened to black. Ethyl acetate (10 mL) was added and the solidswere removed by vacuum filtration through a glass frit. The liquor waswashed with water (10 mL). The organic phase was dried over magnesiumsulfate, filtered, and concentrated by rotary evaporator to give a tansolid. The product was recrystallized from ethyl acetate/hexanes to give389 mg (61%) of the title compound as a white powder. MS (ESI+) m/z427.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 3.74 (s, 3H), 4.16 (br s, 1H), 4.42 (brs, 1H), 7.04-7.09 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.24 (dd, J=7.5, 1.7Hz, 1H), 7.36 (dd, J=7.8, 4.7 Hz, 1H), 7.40-7.46 (m, 1H), 7.52-7.68 (m,3H), 7.73 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (dd, J=8.0, 1.9 Hz, 1H), 8.50(dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1541-(2,3-dichlorophenyl)-N-{[2-(3,4-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 154A 2-(3,4-difluorophenyl)nicotinonitrile

Prepared in 77% yield from 2-chloro-3-cyanopyridine and3,4-difluorophenylboronic acid according to the procedure described forExample 153A. ¹H NMR (DMSO-d₆) δ 7.62-7.71 (m, 2H), 7.74-7.79 (m, 1H),7.95 (ddd, J=11.7, 7.8, 2.2 Hz, 1H), 8.46 (dd, J=7.8, 1.7 Hz, 1H) 8.94(dd, J=5.1, 1.7 Hz, 1H).

EXAMPLE 154B1-(2,3-dichloro-phenyl)-3-[2-(3,4-difluoro-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 77% yield from Example 154A according to the proceduredescribed for Example 153B. MS (ESI+) m/z 423.9 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 4.73 (s, 2H), 7.32-7.64 (m, 7H), 7.84 (dd, J=7.8, 1.4 Hz, 1H), 8.35(s, 1H), 8.56 (dd, J=4.6, 1.5 Hz, 1H), 9.48 (s, 1H).

EXAMPLE 154C1-(2,3-dichlorophenyl)-N-{[2-(3,4-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 60% yield from Example 154B according to the proceduredescribed for Example 153C. MS (ESI+) m/z 432.9 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 4.52 (d, J=5.8 Hz, 1H), 7.41-7.46 (m, 2H), 7.50-7.73 (m, 5H), 7.87(dd, J=7.8, 1.7 Hz, 1H), 7.95 (dd, J=7.8, 1.7 Hz, 1H), 8.56 (dd, J=4.7,1.7 Hz, 1H).

EXAMPLE 1551-(2,3-dichlorophenyl)-N-{[2-(2-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 155A 2-(2-fluoro-phenyl)-nicotinonitrile

Prepared in 74% yield from 2-chloro-3-cyanopyridine and2-fluorophenylboronic acid according to the procedure described forExample 153A. MS (ESI+) m/z 199.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.22-7.34 (m,2H), 7.42-7.55 (m, 2H), 7.57-7.63 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H),8.91 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 155B1-(2,3-Dichloro-phenyl)-3-[2-(2-fluoro-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 99% yield from Example 155A according to the proceduredescribed for Example 153B. MS (ESI+) m/z 406.0 (M+H)⁺; ¹H NMR (CDCl₃) δ4.85 (d, J=5.4 Hz, 2H), 6.46 (br s, 1H), 7.06-7.26 (m, 3H), 7.35-7.46(m, 5H), 7.64 (Br s, 1H), 8.02 (d, J=7.8 Hz, 1H), 8.67 (br s, 1H).

EXAMPLE 155C1-(2,3-dichlorophenyl)-N-{[2-(2-fluorophenyl)pyridin-3-yl]methyl}1H-tetrazol-5-amine

Prepared in 37% yield from Example 155B according to the proceduredescribed for Example 153C. MS (ESI+) m/z 414.9 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 4.36 (d, J=5.8 Hz, 2H), 7.30-7.36 (m, 2H), 7.43-7.53 (m, 3H),7.61-7.68 (m, 3H), 7.84 (dd, J=8.0, 1.5 Hz, 1H), 7.94 (dd, J=7.8, 1.7Hz, 1H), 8.57 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1561-(2,3-dichlorophenyl)-N-({2-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 156A 2-(3-trifluoromethoxyphenyl)-nicotinonitrile

Prepared in 91% yield from 2-chloro-3-cyanopyridine and3-trifluoromethoxyphenylboronic acid according to the proceduredescribed for Example 153A. MS (ESI−) m/z 264.9 (M+H)⁺; ¹H NMR (CDCl₃) δ7.37-7.45 (m, 2H), 7.57 (dd, J=8.0, 8.0 Hz, 1H), 7.82 (br s, 1H), 7.91(d, J=7.8 Hz, 1H), 8.11 (dd, J=7.8, 1.7 Hz, 1H), 8.90 (dd, J=4.7, 1.7Hz, 1H).

EXAMPLE 156B1-(2,3-Dichloro-phenyl)-3-[2-(3-trifluoromethoxy-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 66% yield from Example 156A according to the proceduredescribed for Example 153B. MS (ESI+) m/z 471.9 (M+H)⁺; ¹H NMR (CDCl₃) δ4.97 (d, J=5.8, 2H), 6.28 (br s, 1H), 7.19-7.27 (m, 4H), 7.36-7.49 (m,5H), 7.63 (br s, 1H), 7.98 (d, J=7.8 Hz, 1H), 8.63 (br s, 1H).

EXAMPLE 156C1-(2,3-dichlorophenyl)-N-({2-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

Prepared in 61% yield from the product of Example 156B according to theprocedure described for Example 153C. MS (ESI+) m/z 480.9 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.74 (d, J=6.1 Hz, 1H), 7.25-7.49 (m, 8H), 7.70 (dd, J=8.1,1.7 Hz, 1H), 7.92 (dd, J=7.8, 1.7 Hz, 1H), 8.64 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1571-(2,3-dichlorophenyl)-N-{[2-(2-methylphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 157A 2-o-olyl-nicotinonitrile

Prepared in 76% yield from 2-chloro-3-cyanopyridine and2-methylphenylboronic acid according to the procedure described forExample 153A. MS (ESI−) m/z 195.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 2.27 (s, 3H),7.29-7.44 (m, 5H), 8.08 (dd, J—7.8, 1.7 Hz, 1H), 8.88 (dd, J=4.7, 1.7Hz, 1H).

EXAMPLE 157B1-(2,3-dichloro-phenyl)-3-(2-o-tolyl-pyridin-3-ylmethyl)thiourea

Prepared in 70% yield from the product of Example 157A according to theprocedure described for Example 153B. MS (ESI+) m/z 401.9 (M+H)⁺; ¹H NMR(CDCl₃) δ 2.04 (s, 3H), 4.66 (br s, 2H), 6.05 (Br s, 1H), 7.04-7.24 (m,8H), 7.28-7.42 (m, 3H), 7.63 (br s, 1H), 7.93 (dd, J=7.8, 1.7 Hz, 1H),8.54 (dd, J=4.9, 1.5 Hz, 1H).

EXAMPLE 157C1-(2,3-dichlorophenyl)-N-{[2-(2-methylphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 16% yield from the product of Example 157B according to theprocedure described for Example 153C. MS (ESI+) m/z 411.0 (M+H)⁺; ¹H NMR(CDCl₃) δ 2.01 (s, 3H), 4.03 (t, J=5.9 Hz, 1H), 4.51 (br s, 2H),7.08-7.31 (m, 6H), 7.42 (dd, J=8.0, 8.0 Hz, 1H), 7.72 (dd, J=8.1, 1.4Hz, 1H), 7.89 (dd, J=7.8, 1.7 Hz, 1H), 8.61 (dd, J=4.9, 1.5 Hz, 1H).

EXAMPLE 1581-(2,3-dichlorophenyl)-N-{[2-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 158A 2-(3-fluorophenyl)nicotinonitrile

Prepared in 91% yield from 2-chloro-3-cyanopyridine and3-fluorophenylboronic acid according to the procedure described forExample 153A. MS (ESI−) m/z 264.9 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.19-7.26 (m,1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 7.47-7.54 (m, 1H), 7.65 (ddd, J=9.7,2.2, 2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.10 (dd, J=8.1, 1.9 Hz, 1H),8.89 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 158B1-(2,3-Dichloro-phenyl)-3-[2-(3-fluoro-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 66% yield from the product of Example 158A according to theprocedure described for Example 153B. MS (ESI+) m/z 406.0 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.95 (d, J=5.1 Hz, 2H), 6.13 (br s, 1H), 7.06-7.26 (m, 5H),7.31-7.41 (m, 3H), 7.59 (br s, 1H), 7.93 (d, J=7.8 Hz, 1H), 8.60 (d,J=4.4 Hz, 1H).

EXAMPLE 158C1-(2,3-dichlorophenyl)-N-{[2-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 64% yield from the product of Example 158B according to theprocedure described for Example 153C. MS (ESI+) m/z 414.9 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.24 (t, J=5.9 Hz, 1H), 4.75 (d, J=5.8 Hz, 2H), 7.06-7.12 (m,1H), 7.14-7.18 (m, 1H), 7.22-7.25 (m, 1H), 7.25-7.26 (m, 1H), 7.31 (dd,J=7.8, 4.7 Hz, 1H), 7.36-7.43 (m, 2H), 7.69 (dd, J=8.1, 1.7 Hz, 1H),7.88 (dd, J=7.8, 1.7 Hz, 1H), 8.61 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1591-(2,3-dichlorophenyl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 159A 2-(4-Trifluoromethoxy-phenyl)-nicotinonitrile

Prepared in 70% yield from 2-chloro-3-cyanopyridine and4-trifluoromethoxyphenylboronic acid according to the proceduredescribed for Example 153A. MS (ESI−) m/z 265.0 (M+H)⁺; ¹H NMR (CDCl₃) δ7.37-7.44 (m, 3H), 7.98-8.03 (m, 2H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 8.89(dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 159B1-(2,3-Dichloro-phenyl)-3-[2-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 63% yield from the product of Example 159A according to theprocedure described for Example 153B. MS (ESI+) m/z 471.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.73 (d, J=4.7 Hz, 2H), 7.35 (dd, J=8.1, 8.0 Hz, 1H),7.45-7.55 (m, 5H), 7.67 (d, J=8.5 Hz, 1H), 7.84 (dd, J=7.8, 1.7 Hz, 1H),8.35 (br s, 1H), 8.57 (dd, J=4.7, 1.7 Hz, 1H), 9.51 (br s, 1H).

EXAMPLE 159C1-(2,3-dichlorophenyl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

Prepared in 48% yield from the product of Example 159B according to theprocedure described for Example 153C. MS (ESI+) m/z 481.0 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.23 (t, J=5.8 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 7.26-7.30 (m,2H), 7.33 (dd, J=7.8, 4.7 Hz, 1H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.53(J=8.8 Hz, 2H), 7.70 (dd, J=8.1, 1.7 Hz, 1H), 7.90 (dd, J=7.8, 1.4 Hz,1H), 8.63 (dd, J=4.7, 1.4 Hz, 1H).

EXAMPLE 1601-(2,3-dichlorophenyl)-N-({2-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 160A 2-(4-Trifluoromethoxy-phenyl)-nicotinonitrile

Prepared in 71% yield from 2-chloro-3-cyanopyridine and2-trifluoromethoxyphenylboronic acid according to the proceduredescribed for Example 153A. MS (ESI−) m/z 264.8 (M+H)⁺; ¹H NMR (CDCl₃) δ7.41-7.48 (m, 3H), 7.54-7.60 (m, 2H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.91(dd, J=5.1, 1.7 Hz, 1H).

EXAMPLE 160B1-(2,3-Dichloro-phenyl)-3-[2-(2-trifluoromethoxy-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 63% yield from the product of Example 160A according to theprocedure described for Example 153B. MS (ESI+) m/z 471.8 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.63 (br s, 1H), 4.88 (br s, 1H), 6.41 (d, J=5.1 Hz, 1H),7.16-7.26 (m, 2H), 7.29-7.49 (m, 6H), 7.68 (br s, 1H), 8.04 (d, J=7.8Hz, 1H), 8.62 (d, J=3.7 Hz, 1H).

EXAMPLE 160C1-(2,3-dichlorophenyl)-N-({2-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

Prepared in 61% yield from the product of Example 160B according to theprocedure described for Example 153C. MS (ESI+) m/z 481.1 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.29 (d, J=4.4 Hz, 2H), 7.43-7.69 (m, 8H), 7.85 (dd, J=8.0,1.5 Hz, 1H), 7.95 (dd, J=8.0, 1.9 Hz, 1H), 8.57 (dd, J=4.6, 1.5 Hz, 1H).

EXAMPLE 161N-{[2-(2-chlorophenyl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 161A 2-(2-chlorophenyl)nicotinonitrile

Prepared in 18% yield from 2-chloro-3-cyanopyridine and2-chlorophenylboronic acid according to the procedure described forExample 153A. MS (ESI−) m/z 215.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.41-7.49 (m,4H), 7.53-7.56 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.90 (dd, J=5.1,1.7 Hz, 1H).

EXAMPLE 161B1-[2-(2-Chloro-phenyl)-pyridin-3-ylmethyl]-3-(2,3-dichloro-phenyl)-thiourea

Prepared in 51% yield from the product of Example 161A according to theprocedure described for Example 153B. MS (ESI+) m/z 421.8 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.55-4.62 (m, 1H), 4.85-4.97 (m, 1H), 6.18 (br s, 1H),7.18-7.42 (m, 8H), 7.56 (br s, 1H), 7.98 (dd, J=7.8, 1.4 Hz, 1H), 8.62(dd, J=4.7, 1.4 Hz, 1H).

EXAMPLE 161CN-{[2-(2-chlorophenyl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 48% yield from the product of Example 161B according to theprocedure described for Example 153C. MS (ESI+) m/z 432.9 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.20-4.24 (m, 1H), 4.48-4.59 (m, 2H), 7.31-7.44 (m, 8H), 7.93(dd, J=7.8, 1.4 Hz, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H).

EXAMPLE 1621-(2,3-dichlorophenyl)-N-{[2-(2-phenoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 162A 2-(2-phenoxy-phenyl)nicotinonitrile

Prepared in 50% yield from 2-chloro-3-cyanopyridine and2-phenoxyphenylboronic acid according to the procedure described forExample 153A. MS (ESI−) m/z 273.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 6.94 (d,J=7.1 Hz, 1H), 7.06-7.11 (m, 3H), 7.20-7.44 (m, 5H), 7.54 (dd, J=7.5,1.7 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H).

EXAMPLE 162B1-(2,3-dichlorophenyl)-3-[2-(2-phenoxyphenyl)-pyridin-3-ylmethyl]thiourea

Prepared in 95% yield from the product of Example 162A according to theprocedure described for Example 153B. MS (ESI+) m/z 479.9 (M+H)⁺.

EXAMPLE 162C1-(2,3-dichlorophenyl)-N-{[2-(2-phenoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 46% yield from the product of Example 162B according to theprocedure described for Example 153C. MS (ESI+) m/z 489.9 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.63 (t, J=5.6 Hz, 1H), 4.70 (br s, 2H), 6.61-6.65 (m, 2H),6.87 (J=8.3, 1.0 Hz, 1H), 6.96-7.01 (m, 1H), 7.12-7.37 (m, 7H), 7.42(dd, J=7.5, 1.7 Hz, 1H), 7.62 (dd, J=8.1, 1.7 Hz, 1H), 7.93 (dd, J=7.8,1.7 Hz, 1H), 8.59 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1631-(2,3-dichlorophenyl)-N-({2-[2-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 163A 2-(2-Trifluoromethyl-phenyl)-nicotinonitrile

Prepared in 30% yield from 2-chloro-3-cyanopyridine and2-trifluoromethylphenylboronic acid according to the procedure describedfor Example 153A. MS (ESI−) m/z 249.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.45-7.50(m, 2H), 7.62-7.72 (m, 2H), 7.83-7.86 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz,1H), 8.87 (dd, J=5.7, 1.7 Hz, 1H).

EXAMPLE 163B1-(2,3-Dichloro-phenyl)-3-[2-(2-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 95% yield from the product of Example 163A according to theprocedure described for Example 153B. MS (ESI+) m/z 455.6 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.38-4.44 (m, 1H), 4.85-4.90 (m, 1H), 6.12 (br s, 1H),7.16-7.43 (m, 5H), 7.50-7.59 (m, 2H), 7.64 (br s, 1H), 7.72-7.75 (m,1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 8.58 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 163C1-(2,3-dichlorophenyl)-N-({2-[2-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

Prepared in 58% yield from the product of Example 163B according to theprocedure described for Example 153C. MS (ESI+) m/z 464.7 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.12 (t, J=5.4 Hz, 1H), 4.37-4.47 (m, 1H), 4.50-4.57 (m, 1H),7.29-7.45 (m, 4H), 7.52-7.62 (m, 2H), 7.70-7.77 (m, 2H), 7.90 (dd,J=8.0, 1.5 Hz, 1H), 8.60 (dd, J=4.9, 1.5 Hz, 1H).

EXAMPLE 1641-(2,3-dichlorophenyl)-N-[(2-thien-2-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 164A 2-thiophen-2-ylnicotinonitrile

To an oven-dried, N₂-purged, 50-mL, round-bottomed flask containing amagnetic stir bar were added cesium fluoride (1.34 g, 8.80 mmol),bis(tri-t-butylphosphine)palladium (66.0 mg, 0.13 mmol), and2-chloro-3-cyanopyridine (559 mg, 4.00 mmol). The flask was sealed witha septum and purged with dry N₂ atmosphere. Anhydrous dioxane (4 mL) wasadded via syringe. Neat 2-(tri-n-butylstannyl)thiophene (2.38 g, 2.02mL, 6.38 mmol) was added via syringe. The reaction mixture was heated to˜90° C. in an oil bath for 18 hours. After cooling to room temperature,ethyl acetate (15 mL) was added and the mixture was filtered through apad of silica. The filtrate was concentrated by rotary evaporator togive a brown oil. The product was purified by flash chromatography(silica gel: 25% ethyl acetate, 75% hexanes=product R_(f)˜0.4) to give˜750 mg of the title compound as a beige solid that was used withoutfurther purification for the next step. MS (ESI−) m/z 186.7 (M+H)⁺; ¹HNMR (CDCl₃) δ 7.19 (dd, J=5.1, 4.0 Hz, 1H), 7.23-7.27 (m, 1H), 7.56 (dd,J=5.1, 1.0 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.27 (d, J=4.1 Hz,1H), 8.74 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 164B1-(2,3-Dichlorophenyl)-3-(2-thiophen-2-ylpyridin-3-ylmethyl)thiourea

Prepared in 95% yield from the product of Example 164A according to theprocedure described for Example 153B. MS (ESI+) m/z 393.6 (M+H)⁺; ¹H NMR(CDCl₃) δ 5.12 (d, J=5.1 Hz, 2H), 6.43 (br s, 1H), 7.09-7.18 (m, 3H),7.20-7.24 (m, 1H), 7.33-7.38 (m, 1H), 7.43 (dd, J=5.1, 1.0 hz, 1H), 7.70(br s, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.58 (br s, 1H).

EXAMPLE 164C1-(2,3-dichlorophenyl)-N-[(2-thien-2-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 29% yield from the product of Example 164B according to theprocedure described for Example 153C. MS (ESI+) m/z 402.6 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.35 (t, J=5.6 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 7.09 (dd,J=5.1, 3.7 Hz, 1H), 7.22 (dd, J=7.2, 4.7 Hz, 1H), 7.26-7.29 (m, 1H),7.34-7.41 (m, 2H), 7.43 (dd, J=5.0, 1.0 Hz, 1H), 7.67 (dd, J=8.0, 1.5Hz, 1H), 7.81 (dd, J=7.8, 1.7 Hz, 1H), 8.58 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1651-(2,3-dichlorophenyl)-N-[(2-thien-3-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 165A 2-thiophen-3-ylnicotinonitrile

To an oven-dried, N₂-purged, 50 mL, round-bottomed flask containing amagnetic stir bar were added potassium fluoride (767 mg, 13.2 mmol),bis(tri-t-butylphosphine)palladium (51.0 mg, 0.10 mmol),tris(dibenzylideneacetone)dipalladium 46 mg, 0.05 mmol),2-chloro-3-cyanopyridine (559 mg, 4.00 mmol), and 3-thiopheneboronicacid (819 mg, 6.4 mmol). The flask was sealed with a septum and purgedwith dry N₂ atmosphere. Anhydrous dioxane (4 mL) was added via syringe.The reaction mixture was heated to ˜90° C. in an oil bath for 18 hours.After cooling to room temperature, ethyl acetate (15 mL) was added andthe mixture was filtered through a pad of silica. The filtrate wasconcentrated by rotary evaporator to give a brown oil. The product waspurified by recrystallization from ethyl acetate/hexanes to give 417 mg(56%) of the title compound as a beige solid. MS (ESI−) m/z 186.9(M+H)⁺; ¹H NMR (CDCl₃) δ 7.30 (7.8, 4.7 Hz, 1H), 7.44 (dd, J=5.3, 2.9Hz, 1H), 7.88 (dd, J=5.1, 1.4 Hz, 1H), 8.03 (dd, J=8.0, 1.9 Hz, 1H),8.29 (dd, J=3.0, 1.4 Hz, 1H), 8.82 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 165B1-(2,3-Dichloro-phenyl)-3-(2-thiophen-3-yl-pyridin-3-ylmethyl)-thiourea

Prepared in 95% yield from the product of Example 165A according to theprocedure described for Example 153B. MS (ESI+) m/z 393.8 (M+H)⁺; ¹H NMR(CDCl₃) δ 5.04 (d, J=5.4 Hz, 2H), 6.38 (br s, 1H), 7.10-7.20 (m, 2H),7.28-7.34 (m, 1H), 7.35-7.39 (m, 3H), 7.57 (br s, 1H), 7.67 (br s, 1H),7.90 (d, J=7.1 Hz, 1H), 8.59 (br s, 1H).

EXAMPLE 165C1-(2,3-dichlorophenyl)-N-[(2-thien-3-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 85% yield from the product of Example 165B according to theprocedure described for Example 153C. MS (ESI+) m/z 402.9 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.23 (t, J=5.6 Hz, 1H), 4.84 (d, J=6.1 Hz, 2H), 7.24-7.28 (m,2H), 7.33 (dd, J=5.1, 1.9 Hz, 1H), 7.37-7.42 (m, 2H), 7.51 (dd, J=3.0,1.4 Hz, 1H), 7.69 (dd, J=8.1, 1.7 Hz, 1H), 7.83 (dd, J=7.8, 1.7 Hz, 1H),8.60 (dd, J=4.9, 1.5 Hz, 1H).

EXAMPLE 166N-(2,3′-bipyridin-3-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 166A [2,3′]Bipyridinyl-3-carbonitrile

Prepared in 84% yield from 2-chloro-3-cyanopyridine and3-(tributylstannyl)pyridine according to the procedure described forExample 164A. MS (ESI+) m/z 182.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.44-7.51 (m,2H), 8.13 (dd, J=7.8, 1.7 Hz, 1H), 8.27-8.31 (m, 1H), 8.77 (d, J=4.7 Hz,1H), 8.93 (dd, J=8.9, 1.9 Hz, 1H), 9.19 (br s, 1H).

EXAMPLE 166B1-[2,3′]Bipyridinyl-3-ylmethyl-3-(2,3-dichloro-phenyl)-thiourea

Prepared in 95% yield from the product of Example 166A according to theprocedure described for Example 153B. MS (ESI+) m/z 388.9 (M+H)⁺; ¹H NMR(CDCl₃) δ 4.95 (d, J=5.4 Hz, 2H), 6.57 (br s, 1H), 7.19 (dd, J=8.1, 1.0Hz, 1H), 7.25-7.28 (m, 1H), 7.33-7.38 (m, 2H), 7.45 (dd, J=7.6, 4.9 Hz,1H), 7.83 (br s, 1H), 7.90-7.95 (m, 2H), 8.62-8.64 (m, 2H), 8.76 (br s,1H).

EXAMPLE 166CN-(2,3′-bipyridin-3-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 54% yield from the product of Example 166B according to theprocedure described for Example 153C. MS (ESI+) m/z 397.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ4.61 (br s, 1H), 4.75 (D, J=5.8 Hz, 2H), 7.31-7.39 (m, 2H),7.42 (dd, J=8.0, 8.0 Hz, 1H), 7.50 (br s, 1H), 7.69 (dd, J=8.1, 1.7 Hz,1H), 7.98 (d, J=7.8 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 8.65 (br s, 1H),8.67 (dd, J=4.7, 1.4 Hz, 1H), 8.77 (Br s, 1H).

EXAMPLE 167N-(2,4′-bipyridin-3-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 167A [2,4′]Bipyridinyl-3-carbonitrile

Prepared in 39% yield from 2-chloro-3-cyanopyridine and4-(tributylstannyl)pyridine according to the procedure described forExample 164A. MS (ESI+) m/z 181.9 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.50 (dd,J=8.1, 4.7 Hz, 1H), 7.88 (d, J=6.4 Hz, 2H), 8.14 (dd, J=8.0, 1.9 Hz,1H), 8.83 (d, J=4.4 Hz, 2H), 8.94 (dd, J=4.9, 1.9 Hz, 1H).

EXAMPLE 167B1-[2,4′]Bipyridinyl-3-ylmethyl-3-(2,3-dichlorophenyl)thiourea

Prepared in 95% yield from the product of Example 167A according to theprocedure described for Example 153B. MS (ESI+) m/z 388.9 (M+H)⁺;

EXAMPLE 167CN-(2,4′-bipyridin-3-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 15% yield from the product of Example 167B according to theprocedure described for Example 153C. MS (ESI+) m/z (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.54 (d, J=5.4 Hz, 2H), 7.48 (dd, J=7.8, 4.7 Hz, 1H),7.59-7.68 (m, 4H), 7.73 (dd, J=5.6 Hz, 1H), 7.89-7.96 (m, 2H), 8.61 (dd,J=4.7, 1.7 Hz, 1H), 8.68-8.70 (m, 2H).

EXAMPLE 1681-(2,3-dichlorophenyl)-N-{[2-(1,3-thiazol-2-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 168A 2-Thiazol-2-yl-nicotinonitrile

Prepared in 39% yield from 2-chloro-3-cyanopyridine and2-(tributylstannyl)thiazole according to the procedure described forExample 164A. MS (ESI+) m/z 187.9 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.44 (dd,J=7.8, 4.7 Hz, 1H), 7.57 (d, J=3.0 Hz, 1H), 8.10-8.14 (m, 2H), 8.80 (d,J=3.4 Hz, 1H).

EXAMPLE 168B1-(2,3-dichloro-phenyl)-3-(2-thiazol-2-ylpyridin-3-ylmethyl)thiourea

Prepared in 57% yield from the product of Example 168A according to theprocedure described for Example 153B. MS (ESI+) m/z 395.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 5.23 (d, J=5.8 Hz, 2H), 7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.43(dd, J=8.0, 8.0 Hz, 1H), 7.48-7.58 (m, 2H), 7.66 (dd, J=8.1, 1.9 Hz,1H), 7.88-7.96 (m, 2H), 8.42 (br s, 1H), 8.57 (dd, J=4.7, 1.4 Hz, 1H),9.74 (br s, 1H).

EXAMPLE 168C1-(2,3-dichlorophenyl)-N-{[2-(1,3-thiazol-2-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 51% yield from the product of Example 168B according to theprocedure described for Example 153C. MS (ESI+) m/z 403.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 5.09 (d, J=6.1 Hz, 2H), 7.49 (dd, J=8.0, 4.6 Hz, 1H), 7.63(dd, J=8.0, 8.0 Hz, 1H), 1.74-7.82 (m, 2H), 7.89-7.92 (m, 2H), 7.96 (dd,J=8.1, 3.5 Hz, 1H), 8.01 (d, J=3.0 Hz, 1H), 8.57 (dd, J=4.6, 1.5 Hz,1H).

EXAMPLE 1691-(2,3-dichlorophenyl)-N-{[5-fluoro-2-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 169A 2-chloro-5-fluoro-nicotinonitrile

To an oven-dried, 250-mL, round-bottomed flask containing a magneticstir bar were added 2-chloro-5-fluoro-nicotinic acid (4.39 g, 25.0 mmol)and anhydrous toluene (50 mL). Thionyl chloride (5.95 g, 3.65 mL, 50mmol) was added, and a reflux condenser with N₂-inlet was attached. Aheating mantle was applied and the solution was heated to reflux for 2hours. After cooling to room temperature, the solvent/volatiles wereremoved by rotary evaporator to give a golden oil. The crude acidchloride was added to a cold (0° C.) solution of ammonium hydroxide, anda white precipitate formed. The precipitate was collected by vacuumfiltration on a glass frit and air dried.

To an oven-dried, 250 mL, round-bottomed flask were added the crude2-chloro-5-fluoronicotinamide (1.05 g, 6.00 mmol) from above, anhydrousdichloromethane (25 mL), and triethylamine (2.12 g, 2.92 mL, 21.0 mmol).The flask was sealed with a septum and cooled to 0° C. in an ice bath.Neat trifluoroacetic anhydride (1.89 g, 1.25 mL, 9.00 mmol) was addedslowly via syringe and the resulting solution was stirred at 0° C. for30 minutes then allowed to warm to room temperature over 1 hour. Water(20 mL) was added, and the mixture was transferred to a separatoryfunnel. The mixture was extracted with dichloromethane (3×20 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated by rotary evaporator to give a golden oil. The productwas purified by flash chromatography (silica gel: 10% ethyl acetate, 90%hexanes—product Rf˜0.3) to give 862 mg (92%) of the title compound as apale yellow solid. ¹H NMR (CDCl₃) δ 8.66 (dd, J=7.8, 3.0 Hz, 1H), 8.82(d, J=2.7 Hz, 1H).

EXAMPLE 169B 5-fluoro-2-(4-fluorophenyl)nicotinonitrile

Prepared in 68% yield from the product of Example 169A and4-fluorophenylboronic acid according to the procedure described forExample 153A. ¹H NMR (DMSO-d₆) δ 7.39-7.45 (m, 2H), 7.87-7.92 (m, 2H),8.58 (dd, J=8.6, 2.9 Hz, 1H), 8.99 (d, J=3.0 Hz, 1H).

EXAMPLE 169C1-(2,3-Dichloro-phenyl)-3-[5-fluoro-2-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 71% yield from the product of Example 169B according to theprocedure described for Example 153B. MS (ESI+) m/z 423.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.72 (d, J=5.1 HZ, 2H), 7.28-7.39 (m, 3H), 7.51-7.59 M, 4H),7.65 (dd, J=9.8, 3.0 Hz, 1H), 8.35 (br s, 1H), 8.56 (d, J=2.7 Hz, 1H),9.61 (br s, 1H).

EXAMPLE 169D1-(2,3-dichlorophenyl)-N-{[5-fluoro-2-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 86% yield from the product of Example 169B according to theprocedure described for Example 153C. MS (ESI+) m/z 432.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.52 (d, J=5.4 Hz, 2H), 7.29-7.35 (m, 2H), 7.59-7.65 (m,3H), 7.71-7.77 (m, 3H), 7.96 (dd, J=8.1, 1.4 Hz, 1H), 8.57 (d, J=3.0 Hz,1H).

EXAMPLE 1701-(2,3-dichlorophenyl)-N-{[2-(2-methoxyphenyl)-6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 170A 2-(2-Methoxy-phenyl)-6-trifluoromethyl-nicotinonitrile

Prepared in 91% yield from 2-chloro-6-trifluoromethylnicotinonitrile and2-methoxyphenylboronic acid according to the procedure described forExample 153A. MS (ESI−) m/z 279.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 3.83 (s, 3H),7.15 (dd, J=7.5, 7.5 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.43 (dd, J=7.4,1.7 Hz, 1H), 7.55-7.63 (m, 2H), 8.12 (d, J=8.1 Hz, 1H), 8.71 (d, J=7.5Hz, 1H).

EXAMPLE 170B1-(2,3-Dichloro-phenyl)-3-[2-(2-methoxy-phenyl)-6-trifluoromethyl-pyridin-3-ylmethyl]-thiourea

Prepared in 53% yield from the product of Example 170A according to theprocedure described for Example 153B. MS (ESI+) m/z 485.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 3.77 (s, 3H), 4.37 (br s, 1H), 4.76 (br s, 1H), 7.10 (dd,J=7.8, 7.8 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.35(dd, J=8.3, 8.1 Hz, 1H), 7.47-7.55 (m, 3H), 7.91-7.98 (m, 2H), 8.28 (brs, 1H), 9.62 (br s, 1H).

EXAMPLE 170C1-(2,3-dichlorophenyl)-N-{[2-(2-methoxyphenyl)-6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 56% yield from the product of Example 170B according to theprocedure described for Example 153C. MS (ESI+) m/z 494.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 3.77 (s, 3H), 4.23 (br s, 1H), 4.48 (br s, 1H), 7.11 (d,J=7.5, 7.5 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.29 (dd, J=7.5, 1.7 Hz,1H), 7.47-7.53 (m, 1H), 7.61 (dd, J=8.1, 9.0 Hz, 1H), 7.76-7.70 (m, 2H),7.95 (dd, J=8.1, 1.7 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H).

EXAMPLE 1711-(2,3-dichlorophenyl)-N-{[2-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 171A 2-(5-Fluoro-2-methoxy-phenyl)-nicotinonitrile

Prepared in 89% yield from 2-chloronicotinonitrile and5-fluoro-2-methoxyphenylboronic acid according to the proceduredescribed for Example 153A. MS (ESI−) m/z 228.9 (M+H)⁺; ¹H NMR (CDCl₃) δ3.86 (s, 3H), 6.98 (dd, J=8.8, 4.0 Hz, 1H), 7.13-7.22 (m, 2H), 7.40 (dd,J=8.0, 4.9 Hz, 1H), 8.04 (dd, J=8.1, 1.7 Hz, 1H), 8.88 (dd, J=5.1, 1.7Hz, 1H).

EXAMPLE 171B1-(2,3-Dichloro-phenyl)-3-[2-(5-fluoro-2-methoxy-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 95% yield from the product of Example 171A according to theprocedure described for Example 153B. MS (ESI+) m/z 435.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 3.54 (s, 3H), 4.79 (br s, 2H), 6.76 (br s, 1H), 6.89 (dd,J=9.2, 4.4 Hz, 1H), 7.03-7.12 (m, 2H), 7.17-7.26 (m, 2H), 7.29-7.44 (m,2H), 7.73 (br s, 1H), 8.11 (d, J=7.1 Hz, 1H), 8.59 (br s, 1H).

EXAMPLE 171C1-(2,3-dichlorophenyl)-N-{[2-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 30% yield from the product of Example 171B according to theprocedure described for Example 153C. MS (ESI+) m/z 444.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 3.73 (s, 3H), 4.21 (br s, 1H), 4.40 (br s, 1H), 7.05-7.14(m, 2H), 7.23-7.30 (m, 1H), 7.39 (dd, J=8.1, 4.7 Hz, 1H), 7.52-7.56 (m,1H), 7.57-7.67 (m, 2H), 7.77 (dd, J=8.0, 1.5 Hz, 1H), 7.94 (dd, J=7.8,1.7 Hz, 1H), 8.51 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1721-(2,3-dichlorophenyl)-N-{[2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 172A 2-(4-fluoro-2-methoxy-phenyl)nicotinonitrile

Prepared in 85% yield from 2-chloronicotinonitrile and4-fluoro-2-methoxyphenylboronic acid according to the proceduredescribed for Example 153A. MS (ESI−) m/z 228.9 (M+H)⁺; ¹H NMR (CDCl₃) δ6.75-6.84 (m, 2H), 7.37 (dd, J=8.0, 4.9 Hz, 1H), 7.44 (dd, J=8.5, 6.8Hz, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H), 8.86 (dd, J=4.9, 1.9 Hz, 1H).

EXAMPLE 172B1-(2,3-Dichloro-phenyl)-3-[2-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 95% yield from the product of Example 172A according to theprocedure described for Example 153B. MS (ESI+) m/z 435.8 (M+H)⁺ ¹H NMR(CDCl₃) δ 3.59 (s, 3H), 4.76 (d, J=5.1 Hz, 1H), 6.50 (br s, 1H),6.63-6.74 (m, 2H), 7.16-7.30 (m, 3H), 7.35-7.41 (m, 3H), 7.68 (br s,1H), 8.03 (d, J=7.5 Hz, 1H), 8.58 (d, J=5.1 Hz, 1H).

EXAMPLE 172C1-(2,3-dichlorophenyl)-N-{[2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 9% yield from the product of Example 172B according to theprocedure described for Example 153C. MS (ESI+) m/z 444.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 3.76 (s, 3H), 4.20 (br s, 1H), 4.39 (br s, 1H), 6.85-6.92(m, 1H), 7.03 (dd, J=11.5, 2.4 Hz, 1H), 7.27 (dd, J=8.5, 7.1 Hz, 1H),7.37 (dd, J=8.0, 4.9 Hz, 1H), 7.55 (dd, J=5.8 Hz, 1H), 7.58-7.66 (m,2H), 7.75 (dd, J=8.0, 1.5 Hz, 1H), 7.94 (dd, J=8.0, 1.9 Hz, 1H), 8.50(dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1731-(2,3-dichlorophenyl)-N-{[2-(2-fluoro-6-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 173A 2-(4-fluoro-2-methoxyphenyl)nicotinonitrile

Prepared in 85% yield from 2-chloronicotinonitrile and2-fluoro-6-methoxyphenylboronic acid according to the proceduredescribed for Example 153A. MS (ESI−) m/z 228.9 (M+H)⁺; ¹H NMR (CDCl₃) δ6.82-6.88 (m, 2H), 7.38-7.46 (m, 2H), 8.07 (dd, J=7.8, 1.7 Hz, 1H), 8.91(dd, J=4.9, 1.9 Hz, 1H).

EXAMPLE 173B1-(2,3-dichlorophenyl)-3-[2-(2-fluoro-6-methoxyphenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 95% yield from the product of Example 153A according to theprocedure described for Example 153B. MS (ESI+) m/z 436.0 (M+H)⁺; ¹H NMR(CDCl₃) δ 3.65 (s, 3H), 4.64-4.71 (m, 1H), 4.78-4.85 (m, 1H), 6.73-6.78(m, 2H), 7.18-7.24 (m, 2H), 7.33-7.38 (m, 3H), 7.45 (dd, J=7.5, 4.7 Hz,1H), 7.86 (br s, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.62 (d, J=4.7 Hz, 1H).

EXAMPLE 173C1-(2,3-dichlorophenyl)-N-{[2-(2-fluoro-6-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 37% yield from the product of Example 173B according to theprocedure described for Example 153C. MS (ESI+) m/z 445.1 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 3.74 (s, 3H), 4.17-4.25 (m, 1H), 4.28-4.36 (m, 1H), 6.92(dd, J=8.8 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 7.38-7.49 (m, 2H), 7.56-7.60(m, 1H), 7.61-7.69 (m, 2H), 7.77 (dd, J=8.0, 1.5 Hz, 1H), 7.94 (dd,J=8.0, 1.9 Hz, 1H), 8.53 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1741-(2,3-dichlorophenyl)-N-{[2-(2,4-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 174A 2-(2,4-difluoro-phenyl)-nicotinonitrile

Prepared in 78% yield from 2-chloronicotinonitrile and2,4-difluorophenylboronic acid according to the procedure described forExample 153A. MS (ESI−) m/z 216.9 (M+H)⁺; ¹H NMR (CDCl₃) δ 6.97-7.09 (m,2H), 7.45 (dd, J=8.0, 4.9 Hz, 1H), 7.57-7.64 (m, 1H), 8.09 (dd, J=8.0,1.9 Hz, 1H), 8.90 (dd, J=5.1, 1.7 Hz, 1H).

EXAMPLE 174B1-(2,3-Dichloro-phenyl)-3-[2-(2,4-difluoro-phenyl)-pyridin-3-ylmethyl]thiourea

Prepared in 95% yield from the product of Example 174A according to theprocedure described for Example 153B. MS (ESI+) m/z 423.8 (M+H)⁺.

EXAMPLE 174C1-(2,3-dichlorophenyl)-N-{[2-(2,4-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 25% yield from the product of Example 174B according to theprocedure described for Example 153C. MS (ESI+) m/z 432.8 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.36 (d, J=5.4 Hz, 2H), 7.19-7.25 (m, 1H), 7.34-7.41 (m,1H), 7.46 (dd, J=7.8, 4.7 Hz, 1H), 7.50-7.58 (m, 1H), 7.58-7.69 (m, 3H),7.86 (dd, J=8.0, 1.5 Hz, 1H), 7.94 (dd, J=7.8, 1.7 Hz, 1H), 8.57 (dd,J=4.7, 1.7 Hz, 1H).

EXAMPLE 1751-(2,3-dichlorophenyl)-N-{[2-(2,3-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 175A 2-(2,3-difluoro-phenyl)-nicotinonitrile

Prepared in 91% yield from 2-chloronicotinonitrile and2,3-difluorophenylboronic acid according to the procedure described forExample 153A. MS (ESI−) m/z 216.9 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.21-7.29 (m,1H), 7.30-7.39 (m, 2H), 7.49 (dd, J=8.0, 4.9 Hz, 1H), 8.12 (dd, J=7.8,1.7 Hz, 1H), 8.92 (dd, J=4.9, 1.9 Hz, 1H).

EXAMPLE 175B1-(2,3-Dichloro-phenyl)-3-[2-(2,3-difluoro-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 56% yield from the product of Example 175A according to theprocedure described for Example 153B. MS (ESI+) m/z 423.8 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.84 (d, J=5.4 Hz, 2H), 6.37 (br s, 1H), 7.123-7.27 (m, 5H),7.35-7.43 (m, 2H), 7.65 (br s, 1H), 8.03 (d, J=7.8 Hz, 1H), 8.66 (br s,1H).

EXAMPLE 175C1-(2,3-dichlorophenyl)-N-{[2-(2,3-difluorophenyl)pyridin-3-yl]methyl}1H-tetrazol-5-amine

Prepared in 59% yield from the product of Example 175B according to theprocedure described for Example 153C. MS (ESI+) m/z 433.1 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.39 (d, J=5.4 Hz, 2H), 7.28-7.35 (m, 2H), 7.47-7.58 (m,2H), 7.60-7.66 (m, 3H), 7.89 (dd, J=7.8, 1.4 Hz, 1H), 7.94 (dd, J=7.5,2.0 Hz, 1H), 8.59 (dd, J=4.6, 1.5 Hz, 1H).

EXAMPLE 1761-(2,3-dichlorophenyl)-N-{[2-(2,5-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 176A 2-(2,5-Difluoro-phenyl)-nicotinonitrile

Prepared in 66% yield from 2-chloronicotinonitrile and2,5-difluorophenylboronic acid according to the procedure described forExample 153A. ¹H NMR (CDCl₃) δ 7.19-7.23 (m, 2H), 7.29-7.34 (m, 1H),7.48 (dd, J=8.0, 4.9 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 8.92 (dd,J=5.1, 1.7 Hz, 1H).

EXAMPLE 176B1-(2,3-Dichloro-phenyl)-3-[2-(2,5-difluoro-phenyl)-pyridin-3-ylmethyl]-thiourea

Prepared in 95% yield from the product of Example 176A according to theprocedure described for Example 153B. MS (ESI+) m/z 423.8 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.86 (d, J=5.4 Hz, 2H), 6.53 (br s, 1H), 7.08-7.23 (m, 4H),7.29-7.46 (m, 3H), 7.70 (br s, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.65 (br s,1H).

EXAMPLE 176C1-(2,3-dichlorophenyl)-N-{[2-(2,5-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 89% yield from the product of Example 176B according to theprocedure described for Example 153C. MS (ESI+) m/z 433.1 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.39 (d, J=5.4 Hz, 2H), 7.32-7.41 (m, 3H), 7.48 (dd, J=8.1,4.7 Hz, 1H), 7.58-7.69 (m, 4H), 7.88 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (dd,J=7.8, 2.0 Hz, 1H), 8.58 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1771-(2,3-dichlorophenyl)-N-{[2-(2,4,6-trifluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 177A 2-(2,4,6-trifluorophenyl)nicotinonitrile

Prepared in 82% yield from 2-chloronicotinonitrile and2,4,6-trifluorophenylboronic acid according to the procedure describedfor Example 153A. MS (ESI+) m/z 235.0 (M+H)⁺; ¹H NMR (CDCl₃) δ 6.83-6.88m, 2H), 7.51 (dd, J=8.0, 4.9 Hz, 1H), 8.12 (dd, J=8.1, 1.7 Hz, 1H), 8.94(dd, J=5.1, 1.7 Hz, 1H).

EXAMPLE 177B1-(2,4,6-trichlorophenyl)-3-[2-(2,5-difluorophenyl)pyridin-3-ylmethyl]thiourea

Prepared in 87% yield from the product of Example 177A according to theprocedure described for Example 153B. MS (ESI+) m/z 442.0 (M+H)⁺ ¹H NMR(CDCl₃) δ 4.78 (d, J=5.8H, 2H), 6.22 (br s, 1H), 6.74-6.79 (m, 2H),7.15-7.23 (m, 2H), 7.29-7.44 (m, 2H), 7.63 (br s, 1H), 8.02 (d, J=6.8Hz, 1H), 8.67 (dd, J=4.9, 1.5 Hz, 1H).

EXAMPLE 177C1-(2,3-dichlorophenyl)-N-{[2-(2,4,6-trifluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 23% yield from the product of Example 177B according to theprocedure described for Example 153C. MS (ESI+) m/z 451.1 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.34 (d, J=5.8 Hz, 1H), 7.34-7.37 (m, 2H), 7.51 (dd, J=8.0,4.9 Hz, 1H), 7.59-7.66 (m, 3H), 7.89 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (dd,J=7.1, 2.7 Hz, 1H), 8.60 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1781-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 178A 2-pyrrolidin-1-yl-nicotinonitrile

To an oven-dried, N₂-purged, 50-mL flask containing a magnetic stir barwere added 2-fluoronicotinonitrile (1.22 g, 10.0 mmol), anhydroustetrahydrofuran (5 mL), and triethylamine (3.04 g, 4.19 mL, 30.0 mmol).The flask was sealed with a septum and cooled to 0° C. in an ice bath.Neat pyrrolidine (1.04 g, 1.24 mmol, 15.0 mmol) was added via syringe.The mixture was stirred at 0° C. for 30 minutes and then allowed to warmto room temperature overnight. Water (10 mL) was added and the mixturewas transferred to a separatory funnel. The mixture was extracted withdichloromethane (3×10 mL). The combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated by rotary evaporator to abrown oil. The product was recrystallized from ethyl acetate/hexanes togive 1.29 g (75%) of the title compound as a tan powder. MS (ESI+) m/z174.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.91-1.95 (m, 4H), 3.63-3.68 (m, 4H),6.68 (dd, J=7.6, 4.6 Hz, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.31 (dd,J=4.7, 2.0 Hz, 1H).

EXAMPLE 178B1-(2,3-Dichloro-phenyl)-3-(2-pyrrolidin-1-yl-pyridin-3-ylmethyl)-thiourea

To a thick-walled pressure bottle were added Raney nickel (˜5 g, wet)and ammonia-saturated methanol (100 mL). The product of Example 178A(866 mg, 5.00 mmol) was added, and the bottle was inserted into a Parrshaker. The bottle was charged with 60 psi of H₂ gas, and the greymixture was shaken under static hydrogen pressure at room temperaturefor 2 hours. After venting, the solids were removed by vacuum filtrationthrough a glass frit covered with a nylon filter. The solvent/volatileswere removed by rotary evaporator to give ˜900 mg a pale green oilcontaining C-(2-pyrrolidin-1-yl-pyridin-3-yl)-methylamine that was usedwithout further purification for the next step.

To an oven-dried, 100-mL, round-bottomed flask containing a magneticstir bar was added the C-(2-pyrrolidin-1-yl-pyridin-3-yl)-methylamine(˜0.71 g, 4.0 mmol) from above. Anhydrous tetrahydrofuran (20 mL) and2-3-dichlorophenylisothiocyanate (1.02 g, 0.71 mL, 5.00 mmol) were addedvia syringe. The flask was sealed with a septum. The mixture was stirredat room temperature overnight. Water (20 mL) was added, and the reactionwas transferred to a separatory funnel. The mixture was extracted withdichloromethane (3×15 mL). The combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated by rotary evaporator togive a brown solid. The product was recrystallized from ethylacetate/hexanes to give 1.31 g (86%) of the title compound as a whitepowder. MS (ESI+) m/z 380.9 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.84-1.88 (m,4H), 3.43-3.48 (m, 4H), 4.69 (br s, 2H), 6.72 (dd, J=7.5 4.7 HZ, 1H),7.35 (dd, J=8.1, 8.0 Hz, 1H), 7.47-7.51 (m, 2H), 7.67 (d, J=7.1 Hz, 1H),8.03 (dd, J=4.7, 1.7 Hz, 1H), 8.31 (br s, 1H), 9.39 (br s, 1H).

EXAMPLE 178C1-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

To an oven-dried, 100-mL, round-bottomed flask containing a magneticstir bar were added the product of Example 178B (1.14 g, 3.00 mmol),sodium azide (585 mg, 9.00 mmol), and anhydrous tetrahydrofuran (30 mL).Neat triethylamine (911 mg, 1.25 mL, 9.00 mmol) was added via syringe.Solid mercury (II) chloride (896 mg, 3.30 mmol) was added in oneportion. A thick, white precipitate formed upon addition of the mercurysalt. The mixture was stirred at room temperature overnight during whichthe solids darkened to black. Ethyl acetate (20 mL) was added and thesolids were removed by vacuum filtration through a glass frit. Theliquor was washed with water (20 mL). The organic phase was dried overmagnesium sulfate, filtered, and concentrated by rotary evaporator togive a tan solid. The product was recrystallized from ethylacetate/hexanes to give 912 mg (78%) of the title compound as a whitepowder. MS (ESI+) m/z 390.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.82-1.88 (m,4H), 3.43-3.48 (m, 4H), 4.49 (d, J=5.4 Hz, 2H), 6.67 (dd, J=7.3, 4.9 Hz,1H), 7.46 (dd, J=7.3, 1.9 Hz, 1H), 7.57-7.63 (m, 2H), 7.93 (dd, J=8.1,1.7 Hz, 1H), 8.00 (dd, J=4.7, 2.0 Hz, 1H).

EXAMPLE 1791-(2,3-dichlorophenyl)-N-[(2-piperidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared by the same methods as 178A-C substituting piperidine forpyrrolidine. MS (ESI+) m/z 404.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.63(m, 6H), 2.97-3.00 (m, 4H), 4.48 (d, J=5.8 Hz, 2H), 6.98 (dd, J=7.6, 4.9Hz, 1H), 7.57-7.67 (m, 3H), 7.73 (J=8.0, 1.7 Hz, 1H), 7.94 (dd, J=8.1,1.7 Hz, 1H), 8.16 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 180N-[(2-azetidin-1-ylpyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 180A 2-azetidin-1-yl-nicotinonitrile

Prepared in 82% yield from 3-cyano-2-fluoropyridine and azetidinehydrochloride according to the procedure described for Example 178A. MS(ESI+) m/z 160.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.28-2.38 (m, 2H), 4.19-4.25(m, 4H), 6.73 (Dd, J=7.6, 4.9 HZ, 1H), 7.92 (dd, J=7.7, 1.8 Hz, 1H),8.30 (dd, J=4.9, 1.9 Hz, 1H).

EXAMPLE 180B1-(2-azetidin-1-yl-pyridin-3-ylmethyl)-3-(2,3-dichloro-phenyl)-thiourea

Prepared in 84% yield from the product of Example 180A according to theprocedure described for Example 178B. MS (ESI+) m/z 367.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 2.20-2.30 (m, 2H), 4.02-4.07 (m, 4H), 4.54 (br s, 2H), 6.73(dd, 7.3, 4.9 Hz, 1H), J=7.32-7.43 (m, 2H), 7.50 (dd, J=8.1, 1.4 Hz,1H), 7.70 (d, J=6.4 Hz, 1H), 8.04 (dd, J=4.7, 1.7 Hz, 1H), 8.32 (br s,1H), 9.42 (br s, 1H).

EXAMPLE 180CN-[(2-azetidin-1-ylpyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 30% yield from the product of Example 180B according to theprocedure described for Example 178C. MS (ESI+) m/z 375.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 2.18-2.28 (m, 2H), 4.01-4.06 (m, 4H), 4.34 (d, J=5.4 Hz,1H), 6.69 (dd, J=7.5 Hz, 4.7 Hz, 1H), 7.39 (dd, J=7.5, 1.7 Hz, 1H),7.55-7.64 (m, 2H), 7.73 (dd, J=7.8 1.9 Hz, 1H), 7.95 (dd, J=8.1, 1.4 Hz,1H), 8.01 (dd, J=4.9, 1.9 Hz, 1H).

EXAMPLE 1811-(2,3-dichlorophenyl)-N-[(3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 181A 2-chloro-3-pyrrolidin-1-ylisonicotinonitrile

Prepared in 94% yield from 2-chloro-4-cyano-3-fluoropyridine andpyrrolidine according to the procedure described for Example 178A. MS(ESI+) m/z 207.9 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.91-1.95 (m, 4H), 3.62-3.67(m, 4H), 7.63 (d, J=4.7 Hz, 1H), 7.98 (d, J=4.7 HZ, 1H).

EXAMPLE 181B1-(2,3-dichloro-phenyl)-3-(3-pyrrolidin-1-yl-pyridin-4-ylmethyl)-thiourea

Prepared in 89% yield from the product of Example 181A according to theprocedure described for Example 178B with the modification that theRaney Nickel reduction of the nitrile was conducted for 4 hours. MS(ESI+) m/z 381.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.88-1.91 (m, 4H), 3.20-3.25(m, 4H), 4.74 (d, J=4.4 Hz, 2H), 7.13 (d, J=4.7 Hz, 1H), 7.33-7.39 (m,1H), 7.52-7.57 (m, 1H), 7.66 (dd, J=8.1, 1.7 Hz, 1H), 8.06 (d, J=4.7 Hz,1H), 8.14 (s, 1H), 8.33 (br s, 1H), 9.55 (br s, 1H).

EXAMPLE 181C1-(2,3-dichlorophenyl)-N-[(3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amine

Prepared in 44% yield from the product of Example 181B according to theprocedure described for Example 178C. MS (ESI+) m/z 390.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.87-1.91 (m, 4H), 3.20-3.25 (m, 4H), 4.49 (D, J=5.8 Hz,2H), 7.14 (D, J=5.1 HZ, 1H), 7.62 (dd, J=8.1, 8.0 Hz, 1H), 7.69-7.71 (m,1H), 7.75 (dd, J=8.1, 1.7 Hz, 1H), 7.96 (dd, J=8.1, 1.7 HZ, 1H), 8.02(d, J=5.1 HZ, 1H), 8.14 (br s, 1H).

EXAMPLE 1821-(2,3-dichlorophenyl)-N-[(5-fluoro-2-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 182A 5-Fluoro-2-pyrrolidin-1-yl-nicotinonitrile

Prepared in 90% yield from the product of Example 169A and pyrrolidineaccording to the procedure described for Example 178A. MS (ESI+) m/z192.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.90-1.96 (m, 4H), 3.61-3.65 (m, 4H),8.05 (dd, J=8.5, 3.0 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).

EXAMPLE 182B1-(2,3-Dichloro-phenyl)-3-(5-fluoro-2-pyrrolidin-1-yl-pyridin-3-ylmethyl)-thiourea

Prepared in 82% yield from the product of Example 182A according to theprocedure described for Example 178B. MS (ESI+) m/z 399.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.85-1.88 (m, 4H), 3.37-3.42 (m, 4H), 4.71 (d, J=3.7 Hz,2H), 7.34-7.39 (m, 2H), 7.53 (dd, J=8.1, 1.4 Hz, 1H), 7.61 (d, J=8.5 Hz,1H), 8.01 (d, J=3.0 Hz, 1H), 8.33 (br s, 1H), 9.55 (br s, 1H).

EXAMPLE 182C1-(2,3-dichlorophenyl)-N-[(5-fluoro-2-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 59% yield from the product of Example 182B according to theprocedure described for Example 178C. MS (ESI+) m/z 407.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.82-1.87 (m, 4H), 3.38-3.42 (m, 4H), 4.49 (d, J=5.4 Hz,2H), 7.40 (dd, J=9.5, 3.0 Hz, 1H), 7.63 (dd, J=8.1, 8.0 Hz, 1H), 7.69(dd, J=5.6, 5.6 Hz, 1H), 7.77 (dd, J=7.8, 1.9 Hz, 1H), 7.96 (dd, J=8.1,1.4 Hz, 1H), 8.00 (d, J=3.0 Hz, 1H).

EXAMPLE 183N-benzyl-3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-amineEXAMPLE 183A 2-benzylaminonicotinonitrile

Prepared in 66% yield from 2-fluoronicotinonitrile and benzylamineaccording to the procedure described for Example 178A. MS (ESI+) m/z210.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.59 (d, J=6.1 Hz, 2H), 6.64 (dd,J=7.6, 4.9 HZ, 1H), 7.16-7.24 (m, 1H), 7.26-7.32 (m, 5H), 7.71 (dd,J=5.9, 5.9 Hz, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.23 (dd, J=4.9, 1.9Hz, 1H).

EXAMPLE 183B1-(2-Benzylamino-pyridin-3-ylmethyl)-3-(2,3-dichloro-phenyl)thiourea

Prepared in 67% yield from the product of Example 183A according to theprocedure described for from Example 178B. MS (ESI+) m/z 416.9 (M+H)⁺;¹H NMR (DMSO-d₆) δ 4.60 (d, J=5.8 Hz, 2H), 4.65 (d, J=4.4 Hz, 1H), 6.53(dd, J=7.1, 5.1 Hz, 1H), 6.71 (dd, J=5.9, 5.9 Hz, 1H), 7.16-7.20 (m,1H), 7.24-7.37 (m, 6H), 7.53 (d, J=8.5 Hz, 2H), 7.90 (dd, J=4.9, 1.9 Hz,1H), 8.30 (br s, 1H), 9.51 (br s, 1H).

EXAMPLE 183CN-benzyl-3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-amine

Prepared in 14% yield from the product of Example 183B according to theprocedure described for Example 178C. MS (ESI+) m/z 425.7 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.36 (d, J=5.8 Hz, 2H), 4.59 (d, J=5.8 Hz, 2H), 6.50-6.55(m, 2H), 7.16-7.21 (m, 1H), 7.27-7.28 (m, 4H), 7.36 (dd, J=7.3, 1.9 Hz,1H), 7.54 (dd, J=5.4, 5.4 Hz, 1H), 7.61 (dd, J=8.0, 8.0 Hz, 1H), 7.74(dd, J=7.8, 1.7 Hz, 1H), 7.89 (dd, J=4.9, 1.9 Hz, 1H), J=7.95 (dd,J=8.1, 1.7 Hz, 1H).

EXAMPLE 1841-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 184A 2-(3,3-difluoro-azetidin-1-yl)-nicotinonitrile

Prepared in 84% yield from 2-fluoronicotinonitrile and3,3-difluoroazetidine hydrochloride according to the procedure describedfor Example 178A. ¹H NMR (DMSO-d₆) δ 4.65 (t, J=12.4 Hz, 4H), 6.94 (dd,J=7.6, 4.9 Hz, 1H). 8.08 (dd, J=7.8, 1.7 Hz, 1H), 8.40 (dd, J=4.9, 1.9Hz, 1H).

EXAMPLE 184B1-(2,3-Dichloro-phenyl)-3-[2-(3,3-difluoro-azetidin-1-yl)-pyridin-3-ylmethyl]-thiourea

Prepared in 65% yield from the product of Example 184A according to theprocedure described for Example 178B. MS (ESI+) m/z 402.6 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.48 (t, J=12.7 Hz, 4H), 4.57 (dd, J=3.7 Hz, 2H), 6.92 (dd,J=7.3, 4.9 Hz, 1H), 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.51-7.56 (m, 2H),7.63 (d, J=9.5 Hz, 1H), 8.12 (dd, J=5.1, 1.7 Hz, 1H), 8.35 (br s, 1H),9.46 (br s, 1H).

EXAMPLE 184C1-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 66% yield from the product of Example 184B according to theprocedure described for Example 178C. MS (ESI+) m/z 411.6 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.36 (d, J=5.8 Hz, 2H), 4.49 (t, J=12.9 Hz, 4H), 6.88 (dd,J=7.5, 4.7 Hz, 1H), 7.53 (dd, J=7.5, 1.7 Hz, 1H), 7.59-7.66 (m, 2H),7.75 (dd, J=8.0, 1.5 Hz, 1H), 7.95 (dd, J=8.1, 1.4 Hz, 1H), 8.10 (dd,J=5.1, 1.7 Hz, 1H).

EXAMPLE 185N-[(2-chloro-3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 185A1-(2-Chloro-3-pyrrolidin-1-yl-pyridin-4-ylmethyl)-3-(2,3-dichloro-phenyl)-thiourea

Prepared in 89% yield from the product of Example 181A according to theprocedure described for Example 178B with the modification that theRaney Nickel reduction of the nitrile was conducted for 45 minutes. MS(ESI+) m/z 414.5 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.94-1.99 (m, 4H), 3.17-3.21(m, 4H), 4.81 (d, J=5.8 Hz, 2H), 7.24 (d, J=5.1 Hz, 1H), 7.37 (dd,J=8.0, 8.0 Hz, 1H), 7.53-7.59 (m, 2H), 8.19 (d, J=4.7 Hz, 1H), 8.32 (brs, 1H), 9.65 (br s, 1H).

EXAMPLE 185BN-[(2-chloro-3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 34% yield from the product of Example 185A according to theprocedure described for Example 178C. MS (ESI+) m/z 423.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.94-1.99 (m, 4H), 3.18-3.22 (m, 4H), 4.59 (d, J=5.8 Hz,1H), 7.28 (d, J=5.1 Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz, 1H), 7.72-7.78 (m,2H), 7.97 (dd, J=8.1, 1.7 Hz, 1H), 8.17 (d, J=4.7 Hz, 1H).

EXAMPLE 186N-[(2-azetidin-1-yl-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 186A 2-Azetidin-1-yl-5-fluoro-nicotinonitrile

Prepared in 78% yield from the product of Example 169A and azetidinehydrochloride according to the procedure described for Example 178A. MS(ESI+) m/z 177.8 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.28-2.38 (m, 2H), 4.17-4.22(m, 4H), 8.07 (dd, J=8.3, 2.9 Hz, 1H), 8.66 (dd, J=8.1, 3.0 Hz, 1H).

EXAMPLE 186B1-(2-Azetidin-1-yl-5-fluoro-pyridin-3-ylmethyl)-3-(2,3-dichloro-phenyl)-thiourea

Prepared in 36% yield from the product of Example 186A according to theprocedure described for Example 178B.

EXAMPLE 186CN-[(2-azetidin-1-yl-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 12% yield from the product of Example 186B according to theprocedure described for Example 178C. MS (ESI+) m/z 393.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 2.19-2.29 (m, 2H), 4.01 (t, J=7.5 Hz, 4H), 4.34 (d, J=5.8Hz, 2H), 7.33 (dd, J=9.3, 2.9 Hz, 1H), 7.61-7.66 (m, 2H), 7.79 (dd,J=8.0, 1.5 Hz, 1H), 7.97 (dd, J=8.1, 1.4 Hz, 1H), 8.01 (d, J=2.7 Hz,1H).

EXAMPLE 1871-(2,3-dichlorophenyl)-N-[(2,5-difluoro-6-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 187A 2,5-Difluoro-6-pyrrolidin-1-yl-nicotinonitrile

Prepared in 57% yield from 2,5,6-Trifluoro-nicotinonitrile andpyrrolidine according to the procedure described for Example 178A. ¹HNMR (DMSO-d₆) δ 1.85-1.93 (m, 4H), 3.55-3.62 (m, 4H), 8.01 (dd, J=12.2,6.8 Hz, 1H).

EXAMPLE 187B1-(2,3-Dichloro-phenyl)-3-(2,5-difluoro-6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-thiourea

Prepared in 32% yield from the product of Example 187A according to theprocedure described for Example 178B. MS (ESI+) m/z 416.7 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.86-1.90 (m, 4H), 3.49-3.53 (m, 4H), 4.52 (d, J=3.4 Hz,2H), 7.35 (dd, J=8.1, 8.0 Hz, 1H), 7.50-7.56 (m, 2H), 7.60 (d, J=7.1 Hz,1H), 8.36 (br s, 1H), 9.42 (br s, 1H).

EXAMPLE 187C1-(2,3-dichlorophenyl)-N-[(2,5-difluoro-6-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 45% yield from the product of Example 187B according to theprocedure described for Example 178C. MS (ESI+) m/z 425.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.85-1.89 (m, 4H), 3.47-3.52 (m, 4H), 4.30 (d, J=5.8 Hz,2H), 7.50 (dd, J=12.6, 7.5 Hz, 1H), 7.56-7.63 (m, 2H), 7.70 (dd, J=7.8,1.7 Hz, 1H), 7.95 (dd, J=8.1, 1.7 Hz, 1H).

EXAMPLE 1881-(2,3-dichlorophenyl)-N-[(2-phenyl-3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 188A 2-Phenyl-3-pyrrolidin-1-yl-isonicotinonitrile

Prepared in 66% yield from the product of Example 181A and phenylboronicacid according to the procedure described for Example 153A. MS (ESI+)m/z 249.8 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.72-1.77 (m, 4H), 3.17-3.21 (m,4H), 7.38-7.52 (m, 6H), 8.14 (d, J=4.7 Hz, 1H).

EXAMPLE 188B1-(2,3-Dichloro-phenyl)-3-(2-phenyl-3-pyrrolidin-1-yl-pyridin-4-ylmethyl)-thiourea

Prepared in 72% yield from the product of Example 188A according to theprocedure described for Example 178B.

EXAMPLE 188C1-(2,3-dichlorophenyl)-N-[(2-phenyl-3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amine

Prepared in 64% yield from the product of Example 188B according to theprocedure described for Example 178C. MS (ESI+) m/z 466.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.70-1.74 (m, 4H), 2.92-2.96 (m, 4H), 4.52 (d, J=6.1 Hz,1H), 7.25 (d, J=4.7 Hz, 1H), 7.39-7.48 (m, 5H), 6.64 (dd, J=8.0, 8.0 Hz,1H), 7.76-7.80 (m, 2H), 7.98 (dd, J=8.1, 1.4 Hz, 1H), 8.33 (d, J=4.7 Hz,1H).

EXAMPLE 189N-[(2-azepan-1-ylpyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 189A 2-azepan-1-yl-nicotinonitrile

Prepared in 67% yield from 2-fluoronicotinonitrile andhexamethyleneimine according to the procedure described for Example178A.

EXAMPLE 189B1-(2-Azepan-1-yl-pyridin-3-ylmethyl)-3-(2,3-dichloro-phenyl)-thiourea

Prepared in 64% yield from the product of Example 189A according to theprocedure described for Example 178B. MS (ESI+) m/z 408.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.56-1.58 (m, 4H), 1.74-1.76 (m, 4H), 3.35-3.39 (m, 4H),4.66 (br s, 2H), 6.86 (dd, J=7.3, 4.9 Hz, 1H), 7.35 (dd, J=8.0, 8.0 Hz,1H), 7.50-7.53 (m, 2H), 7.64 (d, J=5.8 Hz, 1H), 8.09 (dd, J=4.7, 1.7 Hz,1H), 8.28 (br s, 1H), 9.47 (br s, 1H).

EXAMPLE 189CN-[(2-azepan-1-ylpyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 70% yield from the product of Example 189B according to theprocedure described for Example 178C. MS (ESI+) m/z 418.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.59-1.62 (m, 4H) 1.73-1.74 (m, 4H), 3.34-3.38 (m, 4H), 4.45(d, J=5.4 Hz, 2H), 6.82 (dd, J=7.5, 4.7 Hz, 1H), 7.52 (dd, J=7.5, 1.7Hz, 1H), 7.58-7.63 (m, 2H), 7.72 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (dd,J=8.1, 1.7 Hz, 1H), 8.07 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 1901-(2,3-dichlorophenyl)-N-{[2-pyrrolidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 190A 2-Pyrrolidin-1-yl-6-trifluoromethyl-nicotinonitrile

Prepared in 67% yield from 2-chloro-6-trifluoromethyl-nicotinonitrileand pyrrolidine according to the procedure described for Example 178A.MS (ESI+) m/z 242.9 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.92-1.97 (m, 4H),3.67-3.72 (m, 4H), 7.07 (d, J=7.8 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H).

EXAMPLE 190B1-(2,3-Dichloro-phenyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-ylmethyl)-thiourea

Prepared in 85% yield from the product of Example 190A according to theprocedure described for Example 178B. MS (ESI+) m/z 448.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.87-1.91 (m, 4H), 3.50-3.55 (m, 4H), 4.79 (s, 2H), 7.13 (d,J=7.8 Hz, 1H), 7.36 (dd, J=8.1, 8.0 Hz, 1H), 7.52 (dd, J=8.1, 1.4 Hz,1H), 7.63 (d, J=7.1 Hz, 1H), 8.36 (br s, 1H), 9.49 (br s, 1H).

EXAMPLE 190C1-(2,3-dichlorophenyl)-N-{[2-pyrrolidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 59% yield from the product of Example 190B according to theprocedure described for Example 178C. MS (ESI+) m/z 457.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.85-1.89 (m, 4H), 3.51-3.55 (m, 4H), 4.58 (d, J=5.1 Hz,1H), 7.07 (d, J=7.8 Hz, 1H), 7.58-7.70 (m, 3H), 7.73 (J=7.8, 1.9 Hz,1H), 7.95 (dd, J=8.1, 1.4 Hz, 1H).

EXAMPLE 191N-benzyl-3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)-N-methylpyridin-2-amineEXAMPLE 191A 2-(benzylmethylamino)nicotinonitrile

Prepared in 62% yield from 2-fluoronicotinonitrile andN-methylbenzylamine according to the procedure described for Example178A. MS (ESI+) m/z 224.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 3.21 (s, 3H), 4.92(s, 2H), 6.80 (dd, J=7.8, 4.8 Hz, 1H), 7.23-7.28 (m, 3H), 7.32-7.37 (m,2H), 8.00 (dd, J=7.8, 2.0 Hz, 1H), 8.36 (dd, J=4.6, 1.9 Hz, 1H).

EXAMPLE 191B1-[2-(benzylmethylamino)-pyridin-3-ylmethyl]-3-(2,3-dichloro-phenyl)thiourea

Prepared in 76% yield from the product of Example 191A according to theprocedure described for Example 178B. MS (ESI+) m/z 430.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ2.69 (s, 3H), 4.29 (br s, 2H), 4.79 (br s, 2H), 7.02 (dd,J=7.5, 4.7 Hz, 1H), 7.22-7.38 (, 6H), 7.53 (d, J=8.1 Hz, 1H), 7.60 (d,J=6.1 Hz, 1H), 8.16 (dd, J=4.7, 1.7 Hz, 1H), 8.37 (br s, 1H), 9.54 (brs, 1H).

EXAMPLE 191CN-benzyl-3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)-N-methylpyridin-2-amine

Prepared in 86% yield from the product of Example 191B according to theprocedure described for Example 178C. MS (ESI+) m/z 439.9 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 2.70 (s, 3H), 4.31 (s, 2H), 4.56 (d, J=5.8 Hz, 2H), 6.98(dd, J=7.5, 4.7 Hz, 1H), 7.22-7.27 (m, 1H), 7.30-7.38 (m, 4H), 7.59-7.64(m, 2H), 7.70-7.74 (m, 2H), 7.95 (dd, J=8.1, 1.7 Hz, 1H), 8.15 (dd,J=4.9, 1.9 Hz, 1H).

EXAMPLE 1921-(2,3-dichloro-4-fluorophenyl)-N-[(6′-fluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 192A 2,3-dichloro-4-fluorobenzoic acid

To an oven-dried, N₂-purged 1-L, round-bottomed flask containing a largemagnetic stir bar were added via syringe anhydrous tetrahydrofuran (200mL) and tetramethylethylenediamine (11.3 mL, 8.72 g, 75.0 mmol). Theflask was cooled to −85° C. (dry ice/anhydrous ether slurry) and thesec-butyllithium/cyclohexane solution (53.6 mL of 1.4 M solution, 75.0mmol) was added via syringe. A solution of commercially available3-chloro-4-fluorobenzoic acid (5.24 g, 30 mmol) in anhydroustetrahydrofuran (10 mL) was added dropwise to the reaction via syringe.The resulting orange/brown slurry was stirred at −85° C. for 2 hours. Asolution of hexachloroethane (28.4 g, 120 mmol) in anhydroustetrahydrofuran (30 mL) was added dropwise to the reaction mixture. Themixture was stirred at −85° C. for 1 hour and then allowed to warm toroom temperature over 4 hours. The solvents/volatiles were removed byrotary evaporator to give a brown semi-solid. Water (150 mL) was added.The mixture was transferred to a separatory funnel and washed with ether(2×100 mL). Hydrochloric acid (1 N) was added via pipette to adjust thepH to ˜1. The mixture was extracted with ethyl acetate (4×100 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated by rotary evaporator to give a tan solid. The productwas recrystallized from ethyl acetate/hexanes to give 4.36 g (70%) ofthe title compound as a fine white powder. MS (ESI−) m/z 206.9 (M−H); ¹HNMR (DMSO-d₆) δ 7.54 (dd, J=8.8, 8.8 Hz, 1H), 7.85 (dd, J=8.8, 5.8 Hz,1H), 13.72 (br s, 1H).

EXAMPLE 192B (2,3-dichloro-4-fluoro-phenyl)-carbamic acid t-butyl ester

To an oven-dried, N₂-purged, 250-mL, round-bottomed flask containing amagnetic stir bar was added the product of Example 192A (3.14 g, 15.0mmol). Anhydrous t-butanol (50 mL) was added via syringe. Triethylamine(2.62 mL, 1.90 g, 18.75 mmol) was added via syringe.Diphenylphosphorylazide (3.45 mL, 4.40 g, 16.5 mmol) was added viasyringe. A reflux condenser with N₂-inlet was attached and a heatingmantle was applied. The golden solution was heated to reflux and stirredfor 8 hours. After cooling to room temperature, the solvent/volatileswere removed by rotary evaporator to give a thick golden oil. Theproduct was purified by flash chromatography (silica gel: 10% ethylacetate, 90% hexanes—product R_(f)˜0.6) to give a 3.57 g (85%) of thetitle compound as a white powder. MS (ESI−) m/z 278.0 (M−H); ¹H NMR(DMSO-d₆) δ 1.45 (s, 9H), 7.42 (dd, J=9.0, 9.0 Hz, 1H), 7.54 (dd, J=9.2,5.8 Hz, 1H), 8.95 (br s, 1H).

EXAMPLE 192C 2,3-dichloro-4-fluoroaniline

To an oven-dried, N₂-purged, 100-mL, round-bottomed flask containing amagnetic stir bar were added the product of Example 192B (3.08 g, 11.0mmol) and dichloromethane (25 mL). The flask was sealed with a septumand cooled to 0° C. in an ice bath. Trifluoroacetic acid (18 mL) wasadded dropwise via syringe. The brown solution was stirred at 0° C. for30 minutes and then allowed to warm to room temperature for 2 hours. Themixture was transferred to a large Erlenmeyer flask and the acid wasneutralized by the careful addition of saturated aqueous sodiumbicarbonate. The mixture was transferred to a separatory funnel andextracted with dichloromethane (3×25 mL). The combined organic extractswere dried over magnesium sulfate, filtered, and concentrated by rotaryevaporator to give a brown semi-solid. The product was purified by flashchromatography (silica gel: 20% ethyl acetate, 80% hexanes, productR_(f)˜0.3) to give 1.49 g (81%) of the title compound as a pink solid.MS (ESI−) m/z 178.0 (M−H); ¹H NMR (DMSO-d₆) δ 5.53 (br s, 2H), 6.77 (dd,J=9.2, 5.1 Hz, 1H), 7.13 (dd, J=9.2, 9.2 Hz, 1H).

EXAMPLE 192D 2,3-dichloro-1-fluorophenylisothiocyanate

To an oven-dried, N₂-purged, 100-mL, round-bottomed flask containing alarge magnetic stir bar were added the product of Example 192C (756 mg,4.20 mmol), dichloromethane (40 mL), and potassium carbonate powder(2.90 g, 21.0 mmol). The flask was sealed with a septum and purged withN₂ atmosphere. Thiophosgene (483 μL, 724 mg, 6.30 mmol) was added viasyringe to form an orange/yellow slurry with white precipitate. Themixture was stirred vigorously at room temperature for 24 hours. Thesolids were removed by vacuum filtration through a glass frit, and thefiltrate was washed with dichloromethane and hexanes. The liquor wasconcentrated by rotary evaporator to give a golden/brown oil. Theproduct was purified by flash chromatography (silica gel: 100% hexanes,product Rf˜0.5) to give the title compound as a colorless oil.

EXAMPLE 192E 6′-fluoro-[2,3′]bipyridinyl-3-carbonitrile

To an oven-dried, N₂-purged, 250-mL, round-bottomed flask containing amagnetic stir bar were added the commercially available2-chloro-3-cyanopyridine (1.25 g, 9.00 mmol), the commercially available2-fluoropyridine-5-boronic acid (845 mg, 6.00 mmol), anddichlorobis(triphenylphosphine)palladium(II) (211 mg, 0.300 mmol). Theflask was sealed with a septum and purged with N₂ atmosphere. Anhydrousdioxane (45 mL) and a N₂-purged solution of cesium carbonate (5.86 g,18.0 mmol) in water (45 mL) were added via syringe. The reaction mixturewas heated to ˜90° C. in an oil bath and stirred for 2 hours. Thereaction was monitored by LC-MS. After cooling to room temperature, thesolvent/volatiles were removed by rotary evaporator to give a thickbrown oil. Water (75 mL) was added and the mixture was transferred to aseparatory funnel. The mixture was extracted with ethyl acetate (4×30mL). The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated by rotary evaporator to give a brown solid.The product was recrystallized from ethyl acetate/hexanes to give 1.01 g(84%) of the title compound as a tan powder. MS (ESI⁺) m/z 200.0 (M+H)⁺;¹H NMR (DMSO-d₆) δ 7.43 (dd, J=8.6, 2.9 Hz, 1H), 7.70 (dd, J=8.1, 5.1Hz, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H), 8.74 (d, J=2.7Hz, 1H), 8.98 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 192F C-(6′-fluoro-[2,3′]bipyridinyl-3-yl)-methylamine

To an argon-purged, thick-walled pressure vessel was added wet Raneynickel (˜250 mg). A solution of ammonia-saturated methanol (20 mL) wasadded. The product of Example 192E (150 mg, 0.750 mmol) was added as asolid. The vessel was inserted into a Parr shaker and was charged with60 psi of H₂ gas. The mixture was shaken at room temperature understatic H₂ pressure for 1 hour. The H₂ gas was vented and the vessel waspurged with argon. The solids were removed by vacuum filtration througha glass frit covered with a nylon filter. The solvent/volatiles wereremoved by rotary evaporator to give the title compound as a pale greenoil that was used without further purification.

EXAMPLE 192G1-(2,3-dichloro-4-fluoro-phenyl)-3-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-thiourea

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar were added the product of Example 192D (111 mg, 0.500mmol) and anhydrous tetrahydrofuran (5 mL). The flask was sealed with aseptum and purged with N₂ atmosphere. A solution of the crude product ofExample 192F (122 mg, 0.600 mmol) in anhydrous tetrahydrofuran (1 mL)was added via syringe. The pale green solution was stirred at roomtemperature overnight. Saturated aqueous sodium bicarbonate (10 mL) wasadded to quench. The mixture was transferred to a separatory funnel andextracted with dichloromethane (3×10 mL). The combined organic extractswere dried over magnesium sulfate, filtered, and concentrated by rotaryevaporator to give a tan solid. The product was recrystallized fromethyl acetate/hexanes to give a 198 mg (93%) of the title compound as awhite powder. MS (ESI⁺) m/z 425.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.72 (d,J=4.7 Hz, 2H), 7.31 (dd, J=8.3, 2.9 Hz, 1H), 7.42-7.50 (m, 3H), 7.85(dd, J=7.8, 1.4 Hz, 1H), 8.14-8.20 (m, 1H), 8.31 (br s, 1H), 8.40 (d,J=2.4 Hz, 1H), 8.59 (dd, J=4.7, 1.4 Hz, 1H), 9.51 (br s, 1H).

EXAMPLE 192H1-(2,3-dichloro-4-fluorophenyl)-N-[(6′-fluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar were added the product of Example 192G (170 mg, 0.400mmol), and sodium azide (78.0 mg, 1.20 mmol). The flask was sealed witha septum and purged with N₂ atmosphere. Anhydrous tetrahydrofuran (5 mL)was added via syringe. Triethylamine (209 μL, 152 mg, 1.50 mmol) wasadded via syringe. The solid mercury (II) chloride (136 mg, 0.500 mmol)was added in one portion and the flask was resealed. A thick, whiteprecipitate formed immediately upon addition of the mercury salt. Themixture was stirred at room temperature overnight and monitored byLC-MS. Ethyl acetate (10 mL) was added, and the solids were removed byvacuum filtration through a glass frit. The solids were washed withethyl acetate. The liquor was transferred to a separatory funnel andwashed with water (10 mL). The organic phase was dried over magnesiumsulfate, filtered, and concentrated by rotary evaporator to give anoff-white solid. The product was recrystallized from ethylacetate/hexanes to give 121 mg (70%) of the title compound as a whitepowder. MS (ESI⁺) m/z 434.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.53 (d, J=5.4Hz, 2H), 7.31 (dd, J=8.5, 2.7 Hz, 1H), 7.46 (dd, J=7.8, 4.7 Hz, 1H),7.67-7.84 (m, 3H), 7.90 (d, J=7.8 Hz, 1H), 8.19-8.25 (m, 1H), 8.44 (brs, 1H), 8.60-8.61 (m, 1H).

EXAMPLE 1931-[2-chloro-4-fluoro-3-(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 193A 2-chloro-4-fluoro-1-nitro-3-(trifluoromethyl)benzene

To a 100-mL, round-bottomed flask containing a magnetic stir bar andcooled to 0° C. in an ice bath were added fuming nitric acid (12.6 mL)and fuming sulfuric acid (12.6 mL). Neat1-chloro-3-fluoro-2-trifluoromethyl-benzene (5.36 g, 26.5 mmol) wasadded dropwise while stirring. The mixture was stirred at 0° C. for 10min and then allowed to warm to room temperature for 30 min. The mixturewas poured into a beaker containing ice (50 g) and then transferred to aseparatory funnel. The mixture was extracted with dichloromethane (3×30mL). The combined organic extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporator to give a brown oil. Theproduct—an inseparable mixture of ˜4.5:12-chloro-4-fluoro-1-nitro-3-trifluoromethyl-benzene:1-chloro-3-fluoro-4-nitro-2-trifluoro-methylbenzene was flashchromatographed (silica gel/10% ethyl acetate in hexanes, productR_(f)=0.5) to give 6.41 g (99%) of the mixture of nitration products inthe aforementioned ratio as a yellow oil. ¹H NMR (CDCl₃) majorregioisomer: δ7.97 (dd, 1H), 7.33 (dd, 1H); ¹H NMR (CDCl₃) minorregioisomer δ 8.18 (dd, 1H), 7.53 (d, 1H).

EXAMPLE 193B 2-chloro-4-fluoro-3-trifluoromethylphenylamine

To a 100-mL, round-bottomed flask containing a large magnetic stir barwere added absolute ethanol (10 mL) and glacial acetic acid (20 mL) andthe mixture from Example 193A (1.46 g, 6.00 mmol). Fine mesh iron powder(1.73 g, 30.0 mmol) was added in portions. A reflux condenser wasattached and a heating mantle was applied. The gray slurry was heated toreflux and stirred for 30 min. After cooling to room temperature, thegray solids were removed by vacuum filtration through a glass frit andthe solids were washed with dichloromethane and methanol. The solutionwas concentrated to a brown oil by rotary evaporator and then dissolvedin 10% methanol in dichloromethane (25 mL). The solution was transferredto a 125 mL separatory funnel and washed with saturated sodiumbicarbonate solution. Solids precipitated so the mixture was againfiltered through a glass frit and then separated. The organic layer wasdried over sodium sulfate, filtered, and concentrated by rotaryevaporator to give a brown oil. Flash chromatography (silica gel/20%ethyl acetate in hexanes) afforded 1.11 g (87%) of a pale yellow oilthat contained mixture of ˜4.5:12-chloro-4-fluoro-3-trifluoromethylaniline:4-chloro-2-fluoro-3-trifluoromethylaniline. The regioisomers could beseparated by careful flash chromatography using a large excess of silicagel and 10% ethyl acetate/90% hexanes.2-Chloro-4-fluoro-3-trifluoromethylphenylamine (major regioisomer): MS(ESI⁺) m/z 211.9 (M−H)⁺; ¹H NMR (DMSO-d₆): δ 7.18 (dd, 1H), 7.10 (dd,1H). 4-Chloro-2-fluoro-3-trifluoromethylphenylamine (minor regioisomer):δ 7.18 (d, 1H), 7.01 (d, 1H).

EXAMPLE 193C C-(2-fluoro-pyridin-3-yl)methylamine

Prepared in 29% yield from 2-fluoro-3-methylpyridine according to theprocedure described for Example 141A.

EXAMPLE 193D1-(2-chloro-4-fluoro-3-trifluoromethyl-phenyl)-3-(2-fluoro-pyridin-3-ylmethyl)-thiourea

Prepared in 32% yield from2-chloro-4-fluoro-3-trifluoromethylphenylamine of Example 193B and theproduct of Example 193C according to the procedures described forExample 192D and Example 192G. MS (ESI+) m/z 381.6 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.73 (br s, 2H), 7.33-7.39 (m, 1H), 7.51 (dd, J=10.8, 9.1Hz, 1H), 7.84-7.86 (m, 2H), 7.98-8.09 (m, 1H), 8.14 (d, J=5.1 Hz, 1H),8.50 (br s, 1H).

EXAMPLE 193E1-[2-chloro-4-fluoro-3-(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 10% yield from the product of Example 193D according to theprocedure described for Example 192H. MS (ESI+) m/z 391.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.52 (d, J=5.4 Hz, 1H), 7.33-7.37 (m, 1H), 7.79-7.86 (m,2H), 7.88-7.94 (m, 1H), 8.15 (d, J=4.7 Hz, 1H), 8.21 (dd, J=9.0, 5.3 Hz,1H).

EXAMPLE 1941-[4-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 194A1-(4-Chloro-2-fluoro-3-trifluoromethyl-phenyl)-3-(2-fluoro-pyridin-3-ylmethyl)thiourea

Prepared in 44% yield from4-chloro-2-fluoro-3-trifluoromethylphenylamine and the product ofExample 193C according to the procedures described for Example 192D andExample 192G. MS (ESI+) m/z 381.9 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.74 (d,J=5.4 Hz, 2H), 7.34-7.40 (m, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.83-7.88 (m,1H), 8.02-8.06 (m, 1H), 8.15 (d, J=4.7 Hz, 1H), 8.66 (br s, 1H), 9.66(br s, 1H).

EXAMPLE 194B1-[4-chloro-2-fluoro-3-(trifluoromethyl-phenyl]-N-[(2-fluoropyridin-3-yl]methyl-1H-tetrazol-5-amine

Prepared in 71% yield from the product of Example 194A according to theprocedure described for Example 192H. MS (ESI+) m/z 391.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.54 (d, J=5.4 Hz, 2H), 7.35 (ddd, J=7.3, 5.1, 1.9 Hz, 1H),7.85-7.96 (m, 3H), 8.10 (d, J=8.5 Hz, 1H), 8.14-8.16 (m, 1H).

EXAMPLE 195N-[(2-fluoropyridin-3-yl)methyl]-1-(2,3,4-trichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 195A1-(2-fluoro-pyridin-3-ylmethyl)-3-(2,3,4-trichloro-phenyl)-thiourea

Prepared in 58% yield from the product of Example 193C and2,3,4-trichloroaniline according to the procedures described for Example192D and Example 192G. MS (ESI+) m/z 363.8 (M+H)⁺; ¹H NMR (DMSO-d₆) δ4.72 (d, J=5.1 Hz, 2H), 7.36 (ddd, J=7.2, 5.0, 1.7 Hz, 1H), 7.63-7.68(m, 2H), 7.84-7.90 (m, 1H), 8.14 (d, J=5.1 Hz, 1H), 8.51 (br s, 1H),9.66 (br s, 1H).

EXAMPLE 195BN-[(2-fluoropyridin-3-yl)methyl]-1-(2,3,4-trichlorophenyl)-1H-tetrazol-5-amine

Prepared in 52% yield from the product of Example 195A according to theprocedures described for Example 192H. MS (ESI+) m/z 374.9 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 4.51 (d, J=5.4 Hz, 2H), 7.35 (ddd, J=7.3, 5.1, 1.9 Hz,1H), 7.76-7.83 (m, 2H), 7.88-7.96 (m, 2H), 8.14-8.16 (m, 1H).

EXAMPLE 196N-[(2-fluoropyridin-3-yl)methyl]-1-(2,3,5-trichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 196A1-(2-fluoro-pyridin-3-ylmethyl)-3-(2,3,5-trichloro-phenyl)-thiourea

Prepared in 55% yield from the product of Example 193C and2,3,5-trichloroaniline according to the procedures described for Example192D and Example 192G. MS (ESI+) m/z 363.8 (M+H)⁺; ¹H NMR (DMSO-d₆) δ4.73 (br s, 2H), 7.37 (ddd, J=7.1, 5.1, 2.0 Hz, 1H), 7.72 (d, J=2.0 Hz,1H), 7.83-7.84 (m, 1H), 7.89 (ddd, J=10.0, 7.6, 2.0 Hz, 1H), 8.15 (d,J=5.1 Hz, 1H), 8.65 (br s, 1H), 9.60 (br s, 1H).

EXAMPLE 196BN-[(2-fluoropyridin-3-yl)methyl]-1-(2,3,5-trichlorophenyl)-1H-tetrazol-5-amine

Prepared in 60% yield from the product of Example 196A according to theprocedures described for Example 192H. MS (ESI+) m/z 372.9 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 4.52 (d, J=5.8 Hz, 2H), 7.35 (ddd, J=7.2, 5.0, 1.7 Hz,1H), 7.85 (dd, J=5.8 Hz, 1H), 7.92 (ddd, J=9.7, 7.5, 2.0 Hz, 1H), 8.07(d, J=2.4 Hz, 1H), 8.14-8.16 (m, 1H), 8.22 (d, J=2.7 Hz, 1H).

EXAMPLE 1971-[2,3-bis(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 197A 2,3-Bis(trifluoromethyl)phenylamine

Prepared from 1-nitro-2,3-bis(trifluoromethyl)benzene according to themethod of Example 193B. MS (ESI−) m/z 228.0 (M−H)⁺; ¹H NMR (DMSO-d₆) δ6.11 (br s, 2H), 7.03 (d, J=7.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.41(dd, J=8.0 Hz, 1H).

EXAMPLE 197B1-(2,3-bis(trifluoromethyl)phenyl)-3-(2-fluoropyridin-3-ylmethyl)thiourea

Prepared in 90% yield from the product of Example 197A and the productof Example 193C according to the procedure described for the product ofExample 192D and Example 192G.

EXAMPLE 197C1-[2,3-bis(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 42% yield from the product of Example 197B according to theprocedures described for Example 192H. MS (ESI+) m/z 407.0 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 4.52 (d, J=5.8 Hz, 2H), 7.35 (ddd, J=7.2, 5.0, 1.7 Hz,1H), 7.83-7.93 (m, 2H), 8.10-8.20 (m, 3H), 8.37 (d, J=7.8 Hz, 1H).

EXAMPLE 1981-(2,3-dichloro-4-fluorophenyl)-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 198A1-(2,3-Dichloro-4-fluoro-phenyl)-3-(2-fluoro-pyridin-3-ylmethyl)-thiourea

Prepared in 84% yield from Example 192D and Example 193C according tothe procedure described for Example 192G. MS (ESI+) m/z 347.8 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 4.71 (d, J=5.4 HZ, 2H), 7.34-7.38 (m, 1H), 7.47 (dd,J=8.8, 8.8 Hz, 1H), 7.55-7.60 (m, 1H), 7.83-7.89 (m, 1H), 8.13 (d, J=4.4Hz, 1H), 8.36 (br s, 1H), 9.60 (br s, 1H).

EXAMPLE 198B1-(2,3-dichloro-4-fluorophenyl)-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 52% yield from the product of Example 198A according to theprocedure described for Example 192H. MS (ESI+) m/z 357.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.51 (d, J=5.4 Hz, 2H), 7.35 (ddd, J=7.2, 5.0, 2.0 Hz, 1H),7.72-7.78 (m, 2H), 7.86-7.94 (m, 2H), 8.15 (d, J=4.4 Hz, 1H).

EXAMPLE 1991-(2,3-dichloro-4-fluorophenyl)-N-[(2-thien-3-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amineEXAMPLE 199A1-(2,3-Dichloro-4-fluoro-phenyl)-3-(2-thiophen-3-yl-pyridin-3-ylmethyl)-thiourea

Prepared in 50% yield from the product of Example 192D and2-thiophen-3-ylnicotinonitrile (Example 165A) according to the 2-stepnitrile reduction and amine-isothiocyanate coupling procedures describedfor Example 153B. MS (ESI+) m/z 412.0 (M+H)⁺.

EXAMPLE 199B1-(2,3-dichloro-4-fluorophenyl)-N-[(2-thien-3-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

Prepared in 46% yield from the product of Example 199A according to theprocedure described for Example 192H. MS (ESI+) m/z 421.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.63 (d, J=5.4 Hz, 2 h) 7.34 (dd, J=8.0 4.6 Hz, 1H), 7.49(dd, J=5.1, 1.9 Hz, 1H), 7.65 (dd, J=4.9, 2.9 Hz, 1H), 7.70-7.73 (m,1H), 7.75 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.1, 1.7 Hz, 1H), 7.83-7.88 (m,2H), 8.53 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 200N-[(2-azetidin-1-yl-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amineEXAMPLE 200A1-(2-Azetidin-1-yl-5-fluoro-pyridin-3-ylmethyl)-3-(2,3-dichloro-4-fluoro-phenyl)thiourea

Prepared in 43% yield from the product of Example 192D and the productof Example 186A according to the 2-step nitrile reduction andamine-isothiocyanate coupling procedures described for Example 186B. MS(ESI+) m/z 403.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.19-2.27 (m, 2H), 3.98-4.03(m, 4H), 4.54 (br s, 2H), 7.28 (dd, J=9.3, 2.9 Hz, 1H), 7.48 (dd, J=8.8,8.8 Hz, 1H), 7.58 (br s, 1H), 8.02 (d, J=2.7 Hz, 1H), 8.27 (br s, 1H).

EXAMPLE 200BN-[(2-azetidin-1-yl-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amine

Prepared in 5% yield from the product of Example 200A according to theprocedure described for Example 192H. MS (ESI+) m/z 412.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 2.19-2.28 (m, 2H), 3.99-4.03 (m, 4H), 4.34 (d, J=5.4 Hz,2H), 7.34 (dd, J=9.3, 2.9 Hz, 1H), 7.60 (dd, J=5.6 Hz, 1H), 7.76 (dd,J=8.8, 8.8 Hz, 1H), 7.93 (dd, J=8.8, 5.1 Hz, 1H), 8.01 (d, J=2.7 Hz,1H).

EXAMPLE 2011-(2,3-dichloro-4-fluorophenyl)-N-{[2-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 201A1-(2,3-Dichloro-4-fluoro-phenyl)-3-[2-(4-methyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-thiourea

Prepared in 86% yield from the product of Example 192D and the productof Example 261B according to the procedure for Example 192G. MS (ESI+)m/z 442.1 (M+H)⁺.

EXAMPLE 201B1-(2,3-dichloro-4-fluorophenyl)-N-{[2-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 58% yield from the product of Example 201A according to theprocedure described for Example 192H. MS (ESI+) m/z 451.1 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.84-1.88 (m, 2H), 2.57-2.67 (m, 4H), 3.38-4.45 (m, 4H),4.44 (dd, J=5.8 Hz, 2H), 6.84 (dd, J=7.5, 4.7 Hz, 1H), 7.53 (dd, J=7.5,2.0 Hz, 1H), 7.59 (dd, J=5.6, 5.6 Hz, 1H), 7.74 (dd. J=8.5, 8.5 Hz, 1H),7.86 (dd, J=9.0, 5.3 Hz, 1H), 8.07 (dd, J=4.7, 1.7 Hz, 1H).

EXAMPLE 202N-(2,3′-bipyridin-3-ylmethyl)-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amineEXAMPLE 202A1-[2,3′]Bipyridinyl-3-ylmethyl-3-(2,3-dichloro-4-fluoro-phenyl)-thiourea

Prepared in 56% yield from the product of Example 192D and[2,3′]bipyridinyl-3-carbonitrile (Example 166A) according to the 2-stepnitrile reduction and amine-isothiocyanate coupling procedures describedfor Example 153B. MS (ESI+) m/z 407.1 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.73(d, J=5.1 Hz, 2H), 7.42-7.54 (m, 4H), 7.85 (dd, J=7.8, 1.7 Hz, 1H),7.94-7.98 (m, 1H), 8.30 (br s, 1H), 8.60 (dd, J=4.6, 1.5 Hz, 1H), 8.65(dd, J=4.7, 1.4 Hz, 1H), 8.73 (d, J=1.7 Hz, 1H), 9.53 (br s, 1H).

EXAMPLE 202BN-(2,3′-bipyridin-3-ylmethyl)-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amine

Prepared in 31% yield from the product of Example 202A according to theprocedure described for Example 192H. MS (ESI+) m/z 416.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.53 (d, J=5.8 Hz, 2H), 7.46 (dd, J=7.8, 4.7 Hz, 1H), 7.52(ddd, J=7.8, 4.9, 0.8 Hz, 1H), 7.68-7.71 (m, 1H), 7.74-7.83 (m, 2H),7.89 (dd, J=8.0, 1.5 Hz, 1H), 7.99-6.03 (m, 1H), 8.61 (dd, J=4.7, 8.7Hz, 1H), 8.65 (dd, J=4.7, 1.7 Hz, 1H), 8.77 (d, J=2.4 Hz, 1H).

EXAMPLE 2031-(2,3-dichlorophenyl)-N-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 203A 2-trifluoromethylnicotinonitrile

To an oven-dried, N₂-purged, 100-mL, round-bottomed flask containing amagnetic stir bar were added copper(I) iodide (1.26 g, 6.6 mmol) andpotassium fluoride (383 mg, 6.6 mmol). The flask was heated to 120° C.for 1 hour under vacuum. After cooling to room temperature,2-iodonicotinonitrile (1.38 g, 6.00 mmol) was added followed by theaddition via syringe of anhydrous dimethylformamide (6 mL) and anhydrousN-methylpyrrolidinone (6 mL). A solution of(trifluoromethyl)trimethylsilane (12 mL of 0.5 M, 6.00 mmol) intetrahydrofuran was added via syringe and the reaction mixture wasstirred at room temperature overnight. Water (20 mL) was added. Themixture was transferred to a separatory funnel and extracted with ether(3×30 mL). The combined organic extracts were washed with ammoniumhydroxide (30 mL), 1N hydrochloric acid (30 mL), and saturated sodiumbicarbonate (30 mL). The ether solution was dried over magnesium sulfateand concentrated by rotary evaporator. The product was purified by flashchromatography (silica gel: 35% ethyl acetate, 65% hexanes, productRf˜0.3) to give 800 mg (77%) of the title compound as a white powder. ¹HNMR (CDCl₃) δ 7.69 (dd, J=8.0, 4.9 Hz, 1H), 8.21 (dd, J=8.0, 1.5 HZ,1H), 8.92 (dd, J=4.7, 9.4 Hz, 1H).

EXAMPLE 203B1-(2,3-dichlorophenyl)-3-(2-trifluoromethyl-pyridin-3-ylmethyl)thiourea

Prepared in 95% yield from 2,3-dichlorophenylisothiocyanate and theproduct of Example 203A according to the procedure described for Example153B. MS (ESI+) m/z 379.9 (M+H)⁺; ¹H NMR (CDCl₃) δ 5.11 (d, J=5.4 Hz,2H), 6.38 (br s, 1H), 7.15-7.28 (m, 1H), 7.29 (d, J=7.8 Hz, 1H),7.34-7.38 (m, 1H), 7.44 (d, J=7.8, 1.7 Hz, 1H), 7.51 (dd, J=5.1, 4.7 Hz,1H), 7.65 (br s, 1H), 8.18 (d, J=7.5 Hz, 1H), 8.63 (d, J=4.7 Hz, 1H).

EXAMPLE 203C1-(2,3-dichlorophenyl)-N-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

Prepared in 34% yield from the product of Example 203B according to theprocedure described for Example 153C. MS (ESI+) m/z 389.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.70 (d, J=5.4 Hz, 2H), 7.64 (dd, J=8.1, 8.1 Hz, 1H), 7.73(dd, J=8.0, 4.6 Hz, 1H), 7.78 (dd, J=8.0, 1.5 Hz, 1H), 7.88 (dd, J=5.8,5.8 Hz, 1H), 7.97 (dd, J=8.1, 1.4 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 8.64(d, J=4.4 Hz, 1H).

EXAMPLE 2041-(2,3-dichlorophenyl)-N-{[1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 204A 2-(4-Methoxy-phenyl)-5-methyl-2H-pyrazole-3-carbonitrile

Prepared in 45% yield from2-(4-methoxy-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid according tothe procedure described for Example 169A. MS (ESI+) m/z 214.0 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 2.29 (s, 3H), 3.83 (s, 3H), 6.95 (s, 1H), 7.10 (d, J=9.0Hz, 2H), 7.49 (d, J=9.1 Hz, 2H).

EXAMPLE 204B1-(2,3-Dichloro-phenyl)-3-[2-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylmethyl]-thiourea

Prepared in 76% yield from 2,3-dichlorophenylisothiocyanate and theproduct of Example 204A according to the procedure described for Example153B. MS (ESI+) m/z 421.1 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.26 (s, 3H), 3.81(s, 3H), 4.65 (s, 2H), 6.25 (s, 1H), 7.05 (d, J=9.0 Hz, 2H), 7.34 (dd,J=8.1, 8.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.46-7.50 (m, 1H), 7.71 (d,J=7.5 Hz, 1H), 8.43 (br s, 1H), 9.41 (br s, 1H).

EXAMPLE 204C1-(2,3-dichlorophenyl)-N-{[1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1H-tetrazol-5-amine

Prepared in 34% yield from the product of Example 204B according to theprocedure described for Example 153C. MS (ESI+) m/z 430.1 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 2.23 (s, 3H), 3.80 (s, 3H), 4.43 (d, J=5.8 Hz, 2H), 6.16 (s,1H), 7.03 (d, J=9.2 Hz, 2H), 7.37 (d, J=9.2 Hz, 2H), 7.57-7.70 (m, 3H),7.93 (dd, J=8.0, 1.5 Hz, 1H).

EXAMPLE 205N-{[1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 205A 2-(4-chlorophenyl)-5-methyl-2H-pyrazole-3-carbonitrile

Prepared in 41% yield from2-(4-chlorophenyl)-5-methyl-2H-pyrazole-3-carboxylic acid according tothe procedure described for Example 169A. MS (ESI+) m/z 217.9 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 2.34 (s, 3H), 7.00 (s, 1H), 7.65 (s, 4H).

EXAMPLE 205B1-(2,3-Dichloro-phenyl)-3-[2-(4-chlorophenyl)-5-methyl-2H-pyrazol-3-ylmethyl]-thiourea

Prepared in 56% yield from 2,3-dichlorophenylisothiocyanate and theproduct of Example 205A according to the procedure described for Example153B.

EXAMPLE 205CN-{[1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Prepared in 68% yield from the product of Example 205B according to theprocedure described for Example 153C. MS (ESI+) m/z 434.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 2.31 (s, 3H), 4.44 (d, J=5.8 Hz, 2H), 6.22 (s, 1H),7.51-7.58 (m, 4H), 7.61 (d, J=8.1H), 7.64-7.66 (m, 1H), 7.69 (dd, J=7.9,1.9 Hz, 1H), 7.93 (dd, J=8.0, 1.5 Hz, 1H).

EXAMPLE 2061-(2,3-dichlorophenyl)-N-{[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 206A 2-Phenyl-5-trifluoromethyl-2H-pyrazole-3-carbonitrile

Prepared according to the method described in: J. Med. Chem. 2000, 43,2975-2981.

EXAMPLE 206B1-(2,3-Dichloro-phenyl)-3-(2-phenyl-5-trifluoromethyl-2H-pyrazol-3-ylmethyl)-thiourea

Prepared in 61% yield from 2,3-dichlorophenylisothiocyanate and theproduct of Example 206A according to the procedure described for Example153B. MS (ESI+) m/z 445.1 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.78 (d, J=5.4 Hz,2H), 6.82 (s, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.40-7.67 (m, 7H), 8.39(br s, 1H), 9.55 (s, 1H).

EXAMPLE 206C1-(2,3-dichlorophenyl)-N-{[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl}-1H-tetrazol-5-amine

Prepared in 85% yield from the product of Example 206B according to theprocedure described for Example 153C. MS (ESI+) m/z 454.0 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 4.60 (d, J=5.4 Hz, 2H), 6.86 (s, 1H), 7.54-7.65 (m, 7H),7.75 (dd, J=5.4, 5.4 Hz, 1H), 7.95 (dd, J=6.8, 2.7 Hz, 1H).

EXAMPLE 2071-(2,3-dichlorophenyl)-5-(2-phenylpyrrolidin-1-yl)-1H-tetrazole

The product of Example 75B (0.1 g) was reacted with 2-phenylpyrrolidine(0.1 g) according to the method of Example 75C to provide 0.029 g of thetitle compound as a white solid. MS (ESI/NH₃) m/z 359 (M+H)⁺. ¹H NMR(DMSO-d₆) δ 1.78-1.9 (m, 4H), 3.3-3.6 (m, 2H), 4.8-5.0 (m, 1H) 6.8-6.9(m, 1H), 7.0-7.2 (m, 5H), 7.59-7.65 (t, 1H), 7.79-7.85 (d, 1H),7.95-7.99 (d, 1H).

EXAMPLE 2085-[2-(4-chlorophenyl)pyrrolidin-1-yl]-1-(2,3-dichlorophenyl)-1H-tetrazole

The compound from Example 75B (0.1 g) was reacted with2-(4-Chloro-phenyl)-pyrrolidine (0.1 g) according to the method ofExample 75C to provide 0.016 g of the title compound as a white solid.MS (ESI/NH₃) m/z 395 (M+H)⁺; ¹H NMR (δ, DMSO-d₆) 1.78-1.9 (m, 4H),3.3-3.6 (m, 2H), 4.8-5.0 (m, 1H) 6.8-6.9 (m, 1H), 7.05-7.19 (m, 4H),7.60-7.65 (t, 1H), 7.79-7.85 (d, 1H), 7.99-8.1 (d, 1H).

EXAMPLE 209N-(cyclohexylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

To a solution of 2,3 dichlorophenylisocyanate (0.1 g, 0.49 mmol) in 5 mLanhydrous tetrahydrofuran was added cyclohexylmethylamine (0.1 g). Thesolution was stirred at room temperature for 2 h when mercury (II)acetate (0.13 g, 0.49 mmol), sodium azide (0.095 g, 1.47 mmol) andtriethylamine (0.148 g, 1.47 mmol) were added. The resulting suspensionwas stirred at room temperature for 12 hours, at which time theprecipitate was filtered through Celite and the organics concentrated invacuo. The crude residue was purified by column chromatography (gradientelution; 25% ethyl acetate/hexanes to 35%) to give 0.09 g of the titlecompound as a sticky foam. MS (ESI/NH₃) m/z 325 (M+H)⁺ ¹H NMR (δ,DMSO-d₆) 0.8-0.95 (m, 2H), 1.05-1.3 (m, 3H), 1.5-1.8 (m, 7H), 3.05-3.12(t, 2H), 7.05-7.17 (t, 1H), 7.58-7.65 (m, 2H), 7.90-7.95 (d, 1H).

EXAMPLE 2101-(2,3-dichlorophenyl)-N-(2,3,6-trifluorobenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,3,6-trifluorobenzylamine (0.079 g) for cyclohexylmethylamine, to give0.040 g of the title compound. MS (ESI/NH₃) m/z 374 (M+H)⁺ ¹H NMR (δ,DMSO-d₆) 4.59-4.60 (d, 2H), 7.05-7.15 (m, 1H), 7.38-7.49 (m 1H),7.56-7.65 (m, 3H), 7.92-7.95 (d, 1H).

EXAMPLE 211N-(2-chloro-3,6-difluorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-chloro-3,6-difluorobenzylamine (0.087 g) for cyclohexylmethylamine, togive 0.07 g of the title compound. MS (ESI/NH₃) m/z 390 (M+H)⁺ ¹H NMR(δ, DMSO-d₆) 4.6-4.67 (d, 2H), 7.25-7.38 (m, 1H), 7.4-7.65 (m, 4H),7.95-7.98 (d, 1H).

EXAMPLE 2121-(2,3-dichlorophenyl)-N-(3-methoxy-2-methylbenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-methyl-3-methoxybenzylamine (0.37 g) for cyclohexylmethylamine, togive 0.24 g of the title compound. MS (ESI/NH₃) m/z 363 (M+H)⁺ ¹H NMR(δ, DMSO-d₆) 2.08 (s, 3H), 3.79 (s, 3H), 4.41-4.5 (d, 2H), 6.82-6.89 (m,2H), 7.02-7.12 (t, 1H), 7.5-7.7 (m, 3H), 7.9-7.94 (d, 1H).

EXAMPLE 2131-(2,3-dichlorophenyl)-N-(5-fluoro-2-methoxybenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-methoxy-5-fluorobenzylamine (0.5 g) for cyclohexylmethylamine, to give0.575 g of the title compound. MS (ESI/NH₃) m/z 367 (M+H)⁺ ¹H NMR (δ,DMSO-d₆) 3.8 (s, 3H), 4.41-4.43 (d, 2H), 6.92-7.02 (m, 3H), 7.59-7.65(m, 2H), 7.75-7.8 (d, 1H), 7.90-7.95 (d, 1H).

EXAMPLE 214 1-(2,3-dichlorophenyl)-N-(2,3-dimethylbenzyl)1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,3-dimethylbenzylamine (0.2 g) for cyclohexylmethylamine, to give 0.13g of the title compound. MS (ESI/NH₃) m/z 347 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 2.19 (s, 3H), 2.22 (s, 3H), 4.42-4.45 (d, 2H), 6.98-7.15 (m,3H), 7.55-7.72 (m, 3H), 7.90-7.95 (d, 2H).

EXAMPLE 2151-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substitutingC-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methylamine (0.3 g) forcyclohexylmethylamine, to give 0.065 g of the title compound. MS(ESI/NH₃) m/z 378 (M+H)⁺; ¹H NMR (δ, DMSO-d₆) 4.21-4.36 (m, 4H)4.42-4.45 (d, 2H), 6.78-6.82 (m, 3H), 7.55-7.72 (m, 3H), 7.90-7.95 (d,2H).

EXAMPLE 216N-(1,3-benzodioxol-4-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substitutingC-benzo[1,3]dioxol-4-yl-methylamine (0.25 g) for cyclohexylmethylamine,to give 0.070 g of the title compound. MS (ESI/NH₃) m/z 363 (M+H)⁺; ¹HNMR (δ, DMSO-d₆) 4.42-4.45 (d, 2H), 6.0 (s, 2H), 6.78-6.82 (m, 3H),7.61-7.72 (m, 3H), 7.90-7.95 (d, 2H).

EXAMPLE 2171-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substitutingC-benzo[1,3]dioxol-6-yl-methylamine (0.08 g) for cyclohexylmethylamine,to give 0.050 g of the title compound. MS (ESI/NH₃) m/z 378 (M+H)⁺; ¹HNMR (δ, DMSO-d₆) 4.21-4.36 (m, 4H) 4.42-4.45 (d, 2H), 6.78-6.82 (m, 3H),7.58-7.68 (t, 2), 7.69-7.71 (d, 1H), 7.93-7.96 (d, 1H).

EXAMPLE 218N-(1,3-benzodioxol-5-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substitutingC-benzo[1,3]dioxol-5-yl-methylamine (0.07 g) for cyclohexylmethylamine,to give 0.070 g of the title compound. MS (ESI/NH₃) m/z 363 (M+H)⁺; ¹HNMR (δ, DMSO-d₆) 4.42-4.45 (d, 2H), 6.0 (s, 2H), 6.79-6.88 (m, 3H),7.58-7.71 (m, 3H), 7.93-7.96 (d, 1H)

EXAMPLE 2191-(2,3-dichlorophenyl)-N-(2,3-dimethoxybenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,3-dimethoxybenzylamine (0.82 g) for cyclohexylmethylamine, to give 1.0g of the title compound. MS (ESI/NH₃) m/z 378 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 3.75 (s, 3H), 3.8 (s, 3H), 4.44-4.52 (d, 2H), 6.8-7.03 (m, 3H),7.55-7.61 (m, 2H), 7.68-7.73 (t, 1H), 7.95-7.99 (d, 1H).

EXAMPLE 2201-(2,3-dichlorophenyl)-N-(3,5-dimethoxybenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting3,5-dimethoxybenzylamine (0.082 g) for cyclohexylmethylamine, to give0.015 g of the title compound. MS (ESI/NH₃) m/z 380 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 3.7 (s, 6H) 4.4-4.45 (d, 2H), 6.83-6.98 (m, 2H), 6.38 (s, 1H),6.5 (s, 2H), 7.57-7.75 (m, 3H), 7.95-7.99 (d, 1H).

EXAMPLE 2211-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,4-dimethoxybenzylamine (0.082 g) for cyclohexylmethylamine, to give0.050 g of the title compound. MS (ESI/NH₃) m/z 380 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 3.7 (s, 3H), 3.8 (s, 3H), 4.35-4.40 (d, 2H), 6.42-6.5 (m, 1H),6.59 (s, 1H), 7.05-7.12 (d, 1H), 7.4-7.43 (t, 1H), 7.58-7.61 (t, 1H),7.62-7.68 (d, 1H), 7.95-7.99 (d, 1H).

EXAMPLE 2221-(2,3-dichlorophenyl)-N-(2,5-dimethylbenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,5-dimethylbenzylamine (0.082 g) for cyclohexylmethylamine, to give0.050 g of the title compound. MS (ESI/NH₃) m/z 348 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 2.2 (s, 6H), 4.39-4.42 (d, 2H), 6.97-7.1 (m, 3H), 7.45-7.77 (m,3H), 7.95-7.99 (d, 1H).

EXAMPLE 223N-(3-chloro-2-methylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-methyl-3-chlorobenzylamine (0.076 g) for cyclohexylmethylamine, togive 0.080 g of the title compound. MS (ESI/NH₃) m/z 367 (M+H)⁺; ¹H NMR(δ, DMSO-d₆) 2.37 (s, 3H), 4.41-4.45 (d, 2H), 7.16-7.20 (t, 1H),7.22-7.25 (d, 1H), 7.31-7.35 (d, 1H), 7.58-7.65 (m, 2H), 7.71-7.78 (d,1H), 7.96-7.99 (d, 1H).

EXAMPLE 224N-(5-chloro-2-methylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-methyl-5-chlorobenzylamine (0.076 g) for cyclohexylmethylamine to give0.060 g of the title compound. MS (ESI/NH₃) m/z 367 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 2.37 (s, 3H), 4.41-4.45 (d, 2H), 7.16-7.20 (m, 2H), 7.22-7.25(s, 1H), 7.58-7.65 (m, 2H), 7.71-7.78 (d, 1H), 7.96-7.99 (d, 1H).

EXAMPLE 2251-(2,3-dichlorophenyl)-N-(2,5-difluorobenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,5-difluorobenzylamine (0.08 g) for cyclohexylmethylamine, to give0.035 g of the title compound. MS (ESI/NH₃) m/z 355 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 4.41-4.45 (d, 2H), 7.05-7.3 (m, 3H), 7.58-7.61 (t, 1H),7.7-7.79 (m, 2H), 7.95-7.99 (d, 1H).

EXAMPLE 226N-(5-chloro-2-fluorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-fluoro-5-chlorobenzylamine (0.078 g) for cyclohexylmethylamine, togive 0.028 g of the title compound. MS (ESI/NH₃) m/z 373 (M+H)⁺; ¹H NMR(δ, DMSO-d₆) 4.48-4.51 (d, 2H), 7.2-7.26 (t, 1H), 7.3-7.41 (m, 2H),7.6-7.64 (t, 1H), 7.65-7.79 (m, 2H), 7.95-7.99 (d, 1H)

EXAMPLE 227N-[2-chloro-5-(trifluoromethyl)benzyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-fluoro-5-chlorobenzylamine (0.102 g) for cyclohexylmethylamine, togive 0.040 g of the title compound. MS (ESI/NH₃) m/z 422 (M+H)⁺; ¹H NMR(δ, DMSO-d₆) 4.61-4.65 (d, 2H), 7.6-7.78 (m, 5H), 7.81-7.88 (t, 1H),7.96-8.0 (d, 1H).

EXAMPLE 2281-(2,3-dichlorophenyl)-N-(2,5-dimethoxybenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,5-dimethoxybenzylamine (0.082 g) for cyclohexylmethylamine, to give0.040 g of the title compound. MS (ESI/NH₃) m/z 380 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 3.65 (s, 3H), 3.78 (s, 3H), 4.40-4.43 (d, 2H), 6.78-6.82 (m,2H), 6.93-6.97 (m, 1H), 7.51-7.56 (t, 1H), 7.59-7.61 (d, 1H), 7.69-7.72(d, 1H), 7.95-7.99 (d, 1H).

EXAMPLE 229N-(2-chloro-6-methylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-chloro-6-methylbenzylamine (0.076 g) for cyclohexylmethylamine, togive 0.07 g of the title compound. MS (ESI/NH₃) m/z 369 (M+H)⁺; ¹H NMR(δ, DMSO-d₆) 2.39 (s, 3H), 4.59-4.61 (d, 2H), 7.15-7.35 (m, 4H),7.42-7.5 (t, 1H), 7.58-7.61 (d, 1H), 7.92-7.96 (d, 2H).

EXAMPLE 2301-(2,3-dichlorophenyl)-N-(2,3-difluorobenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2,3-difluorobenzylamine (0.07 g) for cyclohexylmethylamine, to give0.025 g of the title compound. MS (ESI/NH₃) m/z 356 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 4.5-4.59 (d, 2H), 7.15-7.4 (m, 3H), 7.58-7.62 (t, 1H), 7.65-7.8(m, 2H), 7.95-7.98 (d, 1H).

EXAMPLE 2311-(2,3-dichlorophenyl)-N-(3-isobutylbenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting3-isobutylbenzylamine (0.125 g) for cyclohexylmethylamine, to give 0.09g of the title compound. MS (ESI/NH₃) m/z 376 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 0.81-0.85 (d, 6H), 1.7-1.81 (m, 1H), 2.38-2.41 (d, 1H),4.41-4.44 (d, 2H), 6.98-7.01 (d, 1H), 7.09-7.12 (m, 2H), 7.19-7.22 (t,1H), 7.58-7.7 (m, 3H), 7.95-7.99 (d, 1H).

EXAMPLE 232N-(2-chlorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-chlorobenzylamine (0.073 g) for cyclohexylmethylamine, to give 0.06 gof the title compound. MS (ESI/NH₃) m/z 354 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)4.51-4.59 (d, 2H), 7.25-7.39 (m, 4H), 7.59-7.62 (t, 1H), 7.7-7.8 (m,2H), 7.95-7.99 (d, 2H).

EXAMPLE 233N-(3-chlorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting3-chlorobenzylamine (0.073 g) for cyclohexylmethylamine, to give 0.06 gof the title compound. MS (ESI/NH₃) m/z 354 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)4.41-4.44 (d, 2H), 7.25-7.39 (m, 4H), 7.59-7.62 (t, 1H), 7.7-7.8 (m,2H), 7.95-7.99 (d, 2H).

EXAMPLE 234N-(4-chlorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting4-chlorobenzylamine (0.069 g) for cyclohexylmethylamine, to give 0.06 gof the title compound. MS (ESI/NH₃) m/z 354 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)4.41-4.44 (d, 2H), 7.25-7.39 (m, 4H), 7.59-7.62 (t, 1H), 7.7-7.8 (m,2H), 7.95-7.99 (d, 2H).

EXAMPLE 2351-(2,3-dichlorophenyl)-N-(2-fluorobenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-fluorobenzylamine (0.61 g) for cyclohexylmethylamine, to give 0.78 gof the title compound. MS (ESI/NH₃) m/z 338 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)4.44-4.52 (d, 2H), 7.15-7.2 (m, 2H), 7.28-7.4 (m, 2H), 7.59-7.61 (t,1H), 7.67-7.78 (m, 2H), 7.95-7.99 (d, 1H).

EXAMPLE 2361-(2,3-dichlorophenyl)-N-(3-fluorobenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting3-fluorobenzylamine (0.61 g) for cyclohexylmethylamine, to give 0.96 gof the title compound. MS (ESI/NH₃) m/z 338 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)4.44-4.52 (d, 2H), 7.05-7.2 (m, 3H), 7.31-7.42 (m, 1H), 7.59-7.61 (t,1H), 7.67-7.78 (m, 2H), 7.95-7.99 (d, 1H).

EXAMPLE 2371-(2,3-dichlorophenyl)-N-(4-fluorobenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting4-fluorobenzylamine (0.61 g) for cyclohexylmethylamine, to give 0.05 gof the title compound. MS (ESI/NH₃) m/z 338 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)4.44-4.52 (d, 2H), 7.05-7.18 (m, 2H), 7.31-7.42 (m, 2H), 7.59-7.65 (t,1H), 7.67-7.78 (m, 2H), 7.95-7.99 (d, 1H).

EXAMPLE 2381-(2,3-dichlorophenyl)-N-(2-methoxybenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-methoxybenzylamine (0.06 g) for cyclohexylmethylamine, to give 0.075 gof the title compound. MS (ESI/NH₃) m/z 350 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)3.8 (s, 3H) 4.4-4.45 (d, 2H), 6.83-6.98 (m, 2H), 7.18-7.22 (m, 2H),7.5-7.55 (t, 1H), 7.58-7.60 (t, 1H), 7365-7.71 (d, 1H), 7.95-7.98 (d,1H).

EXAMPLE 2391-(2,3-dichlorophenyl)-N-(3-methoxybenzyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting3-methoxybenzylamine (0.067 g) for cyclohexylmethylamine, to give 0.06 gof the title compound. MS (ESI/NH₃) m/z 350 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)3.79 (s, 3H), 4.49-4.52 (d, 2H), 6.8-6.92 (m, 3H), 7.2-7.3 (m, 1H),7.6-7.72 (m, 3H), 7.98-8.0 (d, 1H).

EXAMPLE 2401-(2,3-dichlorophenyl)-N-[2-(trifluoromethyl)benzyl]-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-trifluoromethylbenzylamine (0.1 g) for cyclohexylmethylamine, to give0.055 g of the title compound. MS (ESI/NH₃) m/z 387 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 4.60-4.62 (d, 2H), 7.4-7.8 (m, 7H), 7.95-7.99 (d, 1H)

EXAMPLE 2411-(2,3-dichlorophenyl)-N-[3-(trifluoromethyl)benzyl]-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting3-trifluoromethylbenzylamine (0.086 g) for cyclohexylmethylamine, togive 0.070 g of the title compound. MS (ESI/NH₃) M/z 387 (M+H)⁺

¹H NMR (δ, DMSO-d₆) 4.58-4.62 (d, 2H), 7.4-7.82 (m, 7H), 7.95-7.99 (d,1H).

EXAMPLE 2421-(2,3-dichlorophenyl)-N-[4-(trifluoromethyl)benzyl]-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting4-trifluoromethylbenzylamine (0.086 g) for cyclohexylmethylamine, togive 0.080 g of the title compound. MS (ESI/NH₃) m/z 387 (M+H)⁺

¹H NMR (δ, DMSO-d₆) 4.58-4.62 (d, 2H), 7.4-7.82 (m, 7H), 7.95-7.99 (d,1H).

EXAMPLE 2431-(2,3-dichlorophenyl)-N-[2-(difluoromethoxy)benzyl]-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-difluoromethoxybenzylamine (0.77 g) for cyclohexylmethylamine, to give1.0 g of the title compound. MS (ESI/NH₃) m/z 386 (M+H)⁺

¹H NMR (δ, DMSO-d₆) 4.55-4.6 (d, 2H), 7.18-7.25 (m, 2H), 7.31-7.41 (m,2H), 7.59-7.75 (m, 3H), 7.96-7.99 (d, 1H).

EXAMPLE 2441-(2,3-dichlorophenyl)-N-[2-(trifluoromethoxy)benzyl]-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-trifluoromethoxybenzylamine (0.094 g) for cyclohexylmethylamine, togive 0.08 g of the title compound. MS (ESI/NH₃) m/z 404 (M+H)⁺

¹H NMR (δ, DMSO-d₆) 4.55-4.63 (d, 2H), 7.3-7.5 (m, 3H), 7.59-7.63 (t,1H), 7.65-7.75 (m, 2H), 7.95-7.99 (d, 1H)

EXAMPLE 2451-(2,3-dichlorophenyl)-N-[3-(trifluoromethoxy)benzyl]-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting3-trifluoromethoxybenzylamine (0.094 g) for cyclohexylmethylamine, togive 0.07 g of the title compound. MS (ESI/NH₃) m/z 404 (M+H)⁺

¹H NMR (δ, DMSO-d₆) 4.53-4.59 (d, 2H), 7.2-7.25 (m, 2H), 7.29-7.36 (d,1H), 7.41-7.46 (t, 1H), 7.59-7.62 (t, 1H), 7.69-7.8 (m, 2H), 7.95-7.99(d, 1H).

EXAMPLE 2461-(2,3-dichlorophenyl)-N-[4-(trifluoromethoxy)benzyl]-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting4-trifluoromethoxybenzylamine (0.094 g) for cyclohexylmethylamine, togive 0.07 g of the title compound. MS (ESI/NH₃) m/z 404 (M+H)⁺

¹H NMR (δ, DMSO-d₆) 4.49-4.56 (d, 2H), 7.2-7.25 (d, 2H), 7.4-7.46 (m,2H), 7.59-7.62 (t, 1H), 7.62-7.72 (m, 2H), 7.94-7.98 (d, 1H)

EXAMPLE 247N-[2-(benzyloxy)benzyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting2-benzyloxybenzylamine (0.5 g) for cyclohexylmethylamine, to give 0.35 gof the title compound. MS (ESI/NH₃) m/z 426 (M+H)⁺

¹H NMR (δ, DMSO-d₆) 4.49-4.56 (d, 2H), 5.19 (s, 2H), 6.85-6.95 (t, 1H),7.0-7.09 (d, 1H), 7.19-7.23 (t, 2H), 7.3-7.7 (m, 10H), 7.95-7.99 (d,1H).

EXAMPLE 2481-(2,3-dichlorophenyl)-N-[2-(methylsulfonyl)benzyl]-1H-tetrazol-5-amine

The product of Example 20 (0.14 g, 0.39 mmol) was dissolved in 10 mLacetone and treated with OXONE (0.94 g, 1.54 mmol) for 24 h. Theresulting slurry was taken up in 100 mL ethyl acetate and washed withwater (3×50 mL), brine (1×50 mL), dried (MgSO₄) and concentrated. Flashchromatography (gradient elution; 25% ethyl acetate/hexanes to 50%) gave0.08 g of the title compound as a white solid. MS (ESI/NH₃) m/z 397(M+H)⁺

¹H NMR (δ, DMSO-d₆); 3.38, (s, 3H), 4.85-4.9 (d, 2H), 7.28-7.78 (m, 4H),7.79-7.81 (m, 3H).

EXAMPLE 249N-{[2-(3-azabicyclo[3.2.2]non-3-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amineEXAMPLE 249A 2-(3-azabicyclo[3.2.2]non-3-yl)nicotinonitrile

To a solution of 2-fluoro-3-cyanopyridine (0.4 g, 3.27 mmol) in 30 mLtetrahydrofuran was added triethylamine (0.66 g, 6.5 mmol) and3-aza-bicyclo[3.2.2]nonane (0.5 g, 3.9 mmol). The reaction was held at50° C. for 12 hours, cooled and diluted with 100 mL ethyl acetate. Theorganics were washed with water (2×50 mL), brine (1×50 mL), dried(MgSO₄) and concentrated. Column chromatography (20% ethylacetate/hexanes) gave the title compound as a solid. MS (ESI/NH₃) m/z126 (M+H)⁺

EXAMPLE 249B [2-(3-azabicyclo[3.2.2]non-3-yl)pyridin-3-yl]methylamine

A solution of the product of Example 249A (0.52 g, 2 mmol), in 40 mLsaturated NH₃/methanol solution was placed in a PAAR hydrogenationpressure vessel and was treated with Raney-Nickel 2300 (0.5 g). Apressure of 60 pounds per square inch of hydrogen gas was applied to thesealed system, and the reaction was allowed to shake for 5 hours. Thepressure was vented and the suspension filtered through a nylonmembrane, washing with methanol. The corresponding solution wasconcentrated to give 0.5 g of the title compound as a crude oil, whichwas used without further purification or characterization. MS (ESI/NH₃)m/z 130 (M+H)⁺.

EXAMPLE 249CN-{[2-(3-azabicyclo[3.2.2]non-3-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

Using the procedure as described in Example 209, substituting product ofExample 249B (0.5 g) for cyclohexylmethylamine, gave 0.14 g of the titlecompound. MS (ESI/NH₃) m/z 444 (M+H)⁺; ¹H NMR (δ, DMSO-d₆) 1.58-1.7 (m,3H), 1.71-1.9 (m, 3H), 2.01-2.1 (m 2H), 3.12-3.3 (m, 2H), 4.59-4.61 (d,2H), 6.95-7.01 (m, 1H), 7.58-7.75 (m, 4H), 7.95-7.99 (d, 1H), 8.14-8.19(m, 1H).

EXAMPLE 2501-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 250A 2-(3,3-difluoropiperidin-1-yl)nicotinonitrile

Using the procedure as described in Example 249A, substituting3,3-difluoropiperizine (0.81 g) for 3-aza-bicyclo[3.2.2]nonane gave 0.8g of the title compound. MS (ESI/NH₃) m/z 224 (M+H)⁺.

EXAMPLE 250B [2-(3,3-difluoropiperidin-1-yl)pyridin-3-yl]methylamine

The compound from Example 250A (0.8 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.59 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 228 (M+H)⁺

EXAMPLE 250C1-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 250B (0.59 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.04 g ofthe title compound. MS (ESI/NH₃) m/z 439 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.78-1.85 (m, 2H), 1.96-2.1 (m, 2H), 2.95-3.05 (m, 2H), 3.21-3.4 (m,2H), 4.42-4.5 (d, 2H), 7.05-7.12 (m, 1H), 7.59-7.78 (m, 3H), 7.95-7.99(d, 1H), 8.2 (s, 1H).

EXAMPLE 2511-(2,3-dichlorophenyl)-N-{[2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 251A 2-(4,4-difluoropiperidin-1-yl)nicotinonitrile

The procedure from Example 249A was followed, substituting4,4-difluoropiperidine (0.77 g) for 3-aza-bicyclo[3.2.2]nonane to give0.86 g of the title compound. MS (ESI/NH₃) m/z 224 (M+H)⁺

EXAMPLE 251B [2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]methylamine

The compound from Example 251A (0.85 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.84 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 228 (M+H)⁺.

EXAMPLE 251C1-(2,3-dichlorophenyl)-N-{[2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 251B (0.3 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.29 g ofthe title compound. MS (ESI/NH₃) m/z 439 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.96-2.2 (m, 4H), 2.95-3.4 (m, 4H), 4.42-4.5 (d, 2H), 7.05-7.12 (m, 1H),7.59-7.78 (m, 4H), 7.95-7.99 (d, 1H), 8.2 (m, 1H).

EXAMPLE 2521-(2,3-dichlorophenyl)-N-({2-[4-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 252A 2-[4-(trifluoromethyl)piperidin-1-yl]nicotinonitrile

The procedure from Example 249A was followed, substituting4-trifluoromethylpiperidine (0.92 g) for 3-aza-bicyclo[3.2.2]nonane togive 0.95 g of the title compound. MS (ESI/NH₃) m/z 256 (M+H)⁺.

EXAMPLE 252B{2-[4-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}methylamine

The compound from Example 252A (0.95 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.9 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 260 (M+H)⁺.

EXAMPLE 252C1-(2,3-dichlorophenyl)-N-({2-[4-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

The compound from Example 252B (0.3 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.1 g ofthe title compound. MS (ESI/NH₃) m/z 471 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.57-1.69 (m, 2H), 1.8-1.9 (m, 2H), 2.75-2.83 (t, 2H), 3.41-3.5 (m, 2H),4.42-4.5 (d, 2H), 6.98-7.07 (m, 1H), 7.59-7.78 (m, 4H), 7.95-7.99 (d,1H), 8.2 (m, 1H).

EXAMPLE 2531-(2,3-dichlorophenyl)-N-{[2-(3-fluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 253A 2-(3-fluoropiperidin-1-yl)nicotinonitrile

The procedure from Example 249A was followed, substituting3-fluoropiperidine (0.73 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.8 gof the title compound. MS (ESI/NH₃) m/z 205 (M+H)⁺.

EXAMPLE 253B [2-(3-fluoropiperidin-1-yl)pyridin-3-yl]methylamine

The compound from Example 253A (0.8 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.87 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 209 (M+H)⁺

EXAMPLE 253C1-(2,3-dichlorophenyl)-N-{[2-(3-fluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 253B (0.3 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.15 g ofthe title compound. MS (ESI/NH₃) m/z 421 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.7-2.0 (m, 4H), 2.90-2.99 (t, 2H), 3.05-3.15 (m, 1H), 4.42-4.5 (d, 2H),4.65-4.72 (m, 1H), 4.82-4.9 (m, 1H), 6.98-7.07 (m, 1H), 7.59-7.78 (m,4H), 7.95-7.99 (d, 1H), 8.2 (m, 1H).

EXAMPLE 2541-(2,3-dichlorophenyl)-N-{[2-(4-fluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 254A 2-(4-fluoropiperidin-1-yl)nicotinonitrile

The procedure from Example 249A was followed, substituting4-fluoropiperidine (0.73 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.75g of the title compound. MS (ESI/NH₃) m/z 205 (M+H)⁺.

EXAMPLE 254B [2-(4-fluoropiperidin-1-yl)pyridin-3-yl]methylamine

The compound from Example 254A (0.74 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.75 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 209 (M+H)⁺

EXAMPLE 254C1-(2,3-dichlorophenyl)-N-{[2-(4-fluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 254B (0.3 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.15 g ofthe title compound. MS (ESI/NH₃) m/z 421 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.87-2.1 (m, 4H), 2.90-2.99 (t, 2H), 3.05-3.25 (m, 3H), 4.42-4.5 (d,2H), 4.75-4.82 (m, 1H), 4.89-4.98 (m, 1H), 6.98-7.07 (m, 1H), 7.59-7.78(m, 4H), 7.95-7.99 (d, 1H), 8.2 (m, 1H).

EXAMPLE 2551-(2,3-dichlorophenyl)-N-({2-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 255A 2-[3-(trifluoromethyl)pyrrolidin-1-yl]nicotinonitrile

The procedure from Example 249A was followed, substituting3-trifluoromethylpyrrolidine (0.2 g) for 3-aza-bicyclo[3.2.2]nonane togive 0.25 g of the title compound. MS (ESI/NH₃) m/z 242 (M+H)⁺.

EXAMPLE 255B{2-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl}methylamine

The compound from Example 255A (0.25 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.2 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 246 (M+H)⁺

EXAMPLE 255C1-(2,3-dichlorophenyl)-N-({2-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

The compound from Example 255B (0.2 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.10 g ofthe title compound. MS (ESI/NH₃) m/z 458 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.94-2.01 (m, 1H), 2.15-2.2 (m, 1H), 3.2-3.4 (m, 2H), 3.43-3.7 (m, 3H),6.78-6.82 (m, 1H), 7.5-7.75 (m, 4H), 7.95-7.99 (d, 1H), 8.02-8.1 (d,1H).

EXAMPLE 2561-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]pyrrolidin-3-olEXAMPLE 256A 2-(3-hydroxypyrrolidin-1-yl)nicotinonitrile

The procedure from Example 249A was followed, substituting3-hydroxypyrrolidine (0.5 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.16g of the title compound. MS (ESI/NH₃) m/z 189 (M+H)⁺

EXAMPLE 256B 1-[3-(aminomethyl)pyridin-2-yl]pyrrolidin-3-ol

The compound from Example 256A (0.15 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.145 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 193 (M+H)⁺.

EXAMPLE 256C1-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]pyrrolidin-3-ol

The compound from Example 256B (0.2 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.11 g ofthe title compound. MS (ESI/NH₃) m/z 406 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.84-2.01 (m, 2H), 3.2-3.4 (m, 1H), 3.43-3.7 (m, 3H), 4.25-4.6 (m, 2H),4.90-4.96 (d, 2H), 6.68-6.72 (m, 1H), 7.41-7.45 (d, 1H), 7.56-7.62 (m,2H), 7.69-7.72 (d, 1H), 7.95-8.01 (m, 2H).

EXAMPLE 2571-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 257A 2-(3,3-difluoropyrrolidin-1-yl)nicotinonitrile

The procedure from Example 249A was followed, substituting3,3-difluoropyrrolidine (0.5 g) for 3-aza-bicyclo[3.2.2]nonane to give0.58 g of the title compound. MS (ESI/NH₃) m/z 209 (M+H)⁺

EXAMPLE 257B [2-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methylamine

The compound from Example 257A (0.58 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.55 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 213 (M+H)⁺.

EXAMPLE 257C1-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 257B (0.23 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.07 g ofthe title compound. MS (ESI/NH₃) m/z 425 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)2.35-2.43 (m, 2H), 3.6-3.7 (t, 2H), 3.7-3.85 (t, 2H), 4.45-4.52 (d, 2H),6.81-6.9 (m, 1H), 7.56-7.75 (m, 4H), 7.95-7.99 (d, 1H), 8.05-8.1 (m,1H).

EXAMPLE 2581-(2,3-dichlorophenyl)-N-{[2-(2-methylpyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 258A 2-(2-methylpyrrolidin-1-yl)nicotinonitrile

The procedure from Example 249A was followed, substituting2-methylpyrrolidine (0.5 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.57g of the title compound. MS (ES/NH₃) M/z 187 (M+H)⁺.

EXAMPLE 258B [2-(2-methylpyrrolidin-1-yl)pyridin-3-yl]methylamine

The compound from Example 258A (0.57 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.56 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 191 (M+H)⁺.

EXAMPLE 258C1-(2,3-dichlorophenyl)-N-{[2-(2-methylpyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 258B (0.56 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.135 g ofthe title compound. MS (ESI/NH₃) m/z 404 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.05-1.09 (d, 3H), 1.4-1.6 (m, 1H), 1.6-1.8 (m, 1H), 1.8-2.0 (m, 1H),2.05-2.19 (m, 1H), 3.1-3.2 (m, 1H), 3.48-3.55 (m, 1H), 3.95-4.02 (m,1H), 4.15-4.23 (m, 1H), 4.38-4.6 (m, 2H), 6.70-6.8 (m, 1H), 7.42-7.8 (m,3H), 7.95-7.99 (d, 1H), 8.03-8.08 (m, 1H).

EXAMPLE 259 1-(2,3-dichlorophenyl)-N-{[2-(2,5-dimethylpyrrolidin1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine EXAMPLE 259A2-(2,5-dimethylpyrrolidin-1-yl)nicotinonitrile

The procedure from Example 259A was followed, substituting racemic2,5-dimethylpyrrolidine (0.5 g) for 3-aza-bicyclo[3.2.2]nonane to givethe title compound. MS (ESI/NH₃) m/z 201 (M+H)⁺.

EXAMPLE 259B [2-(2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl]methylamine

The compound from Example 259A (0.76 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.6 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 205 (M+H)⁺.

EXAMPLE 259C1-(2,3-dichlorophenyl)-N-{[2-(2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 259B (0.6 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.085 g ofthe title compound. MS (ESI/NH₃) m/z 404 (M+H)⁺.

EXAMPLE 2601-(2,3-dichlorophenyl)-N-{[2-(1,4-oxazepan-4-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 260A 2-(1,4-oxazepan-4-yl)nicotinonitrile

The procedure from Example 249A was followed, substitutinghomomorpholine (0.7 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.73 g ofthe title compound. MS (ESI/NH₃) m/z 203 (M+H)⁺.

EXAMPLE 260B [2-(1,4-oxazepan-4-yl)pyridin-3-yl]methylamine

The compound from Example 260A (0.73 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.7 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 207 (M+H)⁺.

EXAMPLE 260C1-(2,3-dichlorophenyl)-N-{[2-(1,4-oxazepan-4-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 260B (0.7 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.12 g ofthe title compound. MS (ESI/NH₃) m/z 420 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.75-1.9 (m, 2H), 3.38-3.42 (m, 4H), 3.68-3.8 (m, 4H), 4.41-4.5 (d, 2H),6.82-6.9 (m, 1H), 7.58-7.78 (m, 4H), 7.95-7.99 (d, 1H), 8.07-8.12 (d,1H).

EXAMPLE 2611-(2,3-dichlorophenyl)-N-{[2-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amineEXAMPLE 261A 2-(4-methyl-1,4-diazepan-1-yl)nicotinonitrile

The procedure from Example 249A was followed, substitutingN-methylhomopiperazine (0.75 g) for 3-aza-bicyclo[3.2.2]nonane to give1.1 g of the title compound. MS (ESI/NH₃) m/z 217 (M+H)⁺.

EXAMPLE 261B [2-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]methylamine

The compound from Example 261A (1.1 g) was subjected to reductionconditions according to the method of Example 249B to provide 1.0 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 221 (M+H)⁺.

EXAMPLE 261C1-(2,3-dichlorophenyl)-N-{[2-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine

The compound from Example 261B (0.67 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.08 g ofthe title compound. MS (ESI/NH₃) m/z 433 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.8-1.9 (t, 1H), 2.23 (s, 3H), 2.56-2.65 (m, 2H), 3.4-3.5 (m, 4H),4.42-4.45 (d, 2H), 6.8-6.85 (m, 1H), 7.5-7.6 (d, 1H), 7.61-7.63 (m, 2H),7.69-7.72 (d, 1H), 7.95-7.99 (d, 1H), 8.05-8.12 (d, 1H).

EXAMPLE 262 tert-butyl4-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,4-diazepane-1-carboxylateEXAMPLE 262A tert-butyl4-(3-cyanopyridin-2-yl)-1,4-diazepane-1-carboxylate

The procedure from Example 249A was followed, substitutingN-tert-butyloxyhomopiperizine (0.75 g) for 3-aza-bicyclo[3.2.2]nonane togive 1.8 g of the title compound. MS (ESI/NH₃) m/z 303 (M+H)⁺.

EXAMPLE 262B tert-butyl4-[3-(aminomethyl)pyridin-2-yl]-1,4-diazepane-1-carboxylate

The compound from Example 262A (1.8 g) was subjected to reductionconditions according to the method of Example 249B to provide 1.8 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 307 (M+H)⁺.

EXAMPLE 262C tert-butyl4-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,4-diazepane-1-carboxylate

The compound from Example 262B (0.67 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.76 g ofthe title compound. MS (ESI/NH₃) m/z 519 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)123-1.4 (d, 9H), 1.76-1.82 (m, 1H), 3.2-3.6 (m, 8H), 4.4-4.46 (d, 2H),6.8-6.85 (m, 1H), 7.5-7.6 (d, 1H), 7.61-7.63 (m, 2H), 7.69-7.72 (d, 1H),7.95-7.99 (d, 1H), 8.05-8.12 (d, 1H).

EXAMPLE 263N-{[2-(1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The compound from Example 262C (0.76 g) was subjected to reactionconditions according to the method of Example 289 to provide 0.195 g ofthe title compound. MS (ESI/NH₃) m/z 419 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)3.2-3.6 (m, 9H), 4.4-4.46 (d, 2H), 6.8-6.85 (m, 1H), 7.5-7.6 (d, 1H),7.61-7.63 (m, 2H), 7.69-7.72 (d, 1H), 7.95-7.99 (d, 1H), 8.05-8.12 (d,1H).

EXAMPLE 264 tert-butyl3-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylateEXAMPLE 264A tert-butyl3-(3-cyanopyridin-2-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

The procedure from Example 249A was followed, substituting3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester WO2001081347 (0.5 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.5 g of thetitle compound. MS (ESI/NH₃) m/z 301 (M+H)⁺.

EXAMPLE 264B tert-butyl3-[3-(aminomethyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

The compound from Example 264A (0.5 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.5 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 305 (M+H)⁺.

EXAMPLE 264C tert-butyl3-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

The compound from Example 264B (0.37 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.45 g ofthe title compound. MS (ESI/NH₃) m/z 515 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.35-1.39 (m, 9H), 2.72-2.94 (dd, 1H), 3.0-3.15 (m, 2H), 3.5-3.7 (m,2H), 3.8-4.0 (m, 2H), 4.4-4.56 (m, 2H), 4.61-4.69 (d, 2H), 6.91-6.99 (m,1H), 7.56-7.77 (4H), 7-95-7.99 (d, 1H), 8.1-8.15 (d, 1H).

EXAMPLE 265N-{[2-(3,6-diazabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The compound from Example 264C (0.45 g) was subjected to reactionconditions according to the method of Example 289 to provide 0.13 g ofthe title compound. MS (ESI/NH₃) m/z 417 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)2.9-3.1 (m, 4H), 3.58-3.8 (4H), 4.5-4.7 (m, 4H), 6.91-6.99 (m, 1H),7.56-7.77 (4H), 7-95-7.99 (d, 1H), 8.1-8.15 (d, 1H).

EXAMPLE 266 benzyl(1S,5S)-6-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylateEXAMPLE 266A benzyl(1S,5S)-6-(3-cyanopyridin-2-yl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The procedure from Example 249A was followed, substituting3S,6R-Diaza-bicyclo[3.2.0]heptane-3-carboxylic acid benzyl esterWO2001081347 (0.18 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.35 g ofthe title compound. MS (ESI/NH₃) m/z 335 (M+H)⁺

EXAMPLE 266B benzyl(1S,5S)-6-[3-(aminomethyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The compound from Example 266A (0.35 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.35 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 339 (M+H)⁺.

EXAMPLE 266C benzyl(1S,5S)-6-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The compound from Example 266B (0.37 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.45 g ofthe title compound. MS (ESI/NH₃) m/z 551 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)3.1-3.4 (m, 1H), 3.7-4.15 (m, 7H), 4.9-5.1 (m, 3H), 6.67-6.72 (m 1H),7.2-7.5 (7H), 7.5-7.61 (m, 2H), 7.7-7.76 (d, 1H), 7.96-7.99 (d, 1H),8.02-8.05 (d, 1H).

EXAMPLE 267N-({2-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]pyridin-3-yl}methyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The compound from Example 266C (0.45 g) was added to a solution of 10%Pd/C (50 mg) in 25 mL anhydrous methanol. Hydrogen gas was introduced tothe system via vacuum cycle (3×) and was held at room temperature for 3d. The catalyst filtered off and the residue purified by preparativeHPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 um particle size)using a gradient of 10% to 100% acetonitrile: 0.1% aqueoustrifluoroacetic acid over 12 min (15 min run time) at a flow rate of 70mL/min to give 0.085 g of the title compound as the trifluoroacetic acidsalt. MS (ESI/NH₃) m/z 418 (M+H)⁺; ¹H NMR (δ, DMSO-d₆) 3.1-3.4 (m, 1H),3.7-4.15 (m, 5H), 4.9-5.1 (m, 3H), 6.67-6.72 (m 1H), 7.5-7.61 (m, 2H),7.7-7.76 (d, 1H), 7.96-7.99 (d, 1H), 8.02-8.05 (d, 1H), 9.2-9.4 (bs,1H), 10.1 (bs, 1H).

EXAMPLE 268 benzyl(1R,5R)-6-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylateEXAMPLE 268A benzyl(1R,5R)-6-(3-cyanopyridin-2-yl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The procedure from Example 249A was followed, substituting3R,6S-Diaza-bicyclo[3.2.0]heptane-3-carboxylic acid benzyl esterWO2001081347 (0.18 g) for 3-aza-bicyclo[3.2.2]nonane to give 0.35 g ofthe title compound. MS (ESI/NH₃) m/z 335 (M+H)⁺.

EXAMPLE 268B benzyl(1R,5R)-6-[3-(aminomethyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The compound from Example 268A (0.35 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.35 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 339 (M+H)⁺.

EXAMPLE 268C benzyl(1R,5R)-6-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The compound from Example 268B (0.37 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.45 g ofthe title compound. MS (ESI/NH₃) m/z 551 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)3.1-3.4 (m, 1H), 3.61-3.69 (m, 2H), 3.8-4.08 (m 2H), 4.1-4.18 (t, 1H),4.25-4.29 (d, 2H), 4.95-5.15 (m, 4H), 6.67-6.72 (m 1H), 7.2-7.5 (7H),7.5-7.61 (m, 2H), 7.7-7.76 (d, 1H), 7.96-7.99 (d, 1H), 8.02-8.05 (d,1H).

EXAMPLE 269N-({2-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-6-yl]pyridin-3-yl}methyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine

The compound from Example 268C (0.45 g) was added to a solution of 10%Pd/C (50 mg) in 25 mL anhydrous methanol. Hydrogen gas was introduced tothe system via vacuum cycle (3×) and was held at room temperature for 3d. The catalyst filtered off and the residue purified by preparativeHPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 um particle size)using a gradient of 10% to 100% acetonitrile:0.1% aqueoustrifluoroacetic acid over 12 min (15 min run time) at a flow rate of 70mL/min to give 0.075 g of the title compound as the trifluoroacetic acidsalt. MS (ESI/NH₃) m/z 418 (M+H)⁺; ¹H NMR (δ, DMSO-d₆) 3.1-3.4 (m, 1H),3.61-3.69 (m, 2H), 3.8-4.08 (m 2H), 4.1-4.18 (t, 1H), 4.25-4.29 (d, 2H),5.1-5.2 (d, 2H), 6.67-6.72 (m 1H), 7.2-7.5 (7H), 7.5-7.61 (m, 2H),7.7-7.76 (d, 1H), 7.96-7.99 (d, 1H), 8.02-8.05 (d, 1H).

EXAMPLE 2701-(2,3-dichlorophenyl)-N-({2-[(3aR,7aS-octahydro-2H-4,7-epoxyisoindol-2-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amineEXAMPLE 270A2-[(3aR,7aS)-octahydro-2H-4,7-epoxyisoindol-2-yl]nicotinonitrile

The procedure from Example 249A was followed, substituting10-Oxa-4-aza-tricyclo[5.2.1.02,6]decane WO2004092134 (0.73 g) for3-aza-bicyclo[3.2.2]nonane to give 0.2 g of the title compound. MS(ESI/NH₃) m/z 242 (M+H)⁺.

EXAMPLE 270B{2-[(3aR,7aS)-octahydro-2H-4,7-epoxyisoindol-2-yl]pyridin-3-yl}methylamine

The compound from Example 270A (0.7 g) was subjected to reductionconditions according to the method of Example 249B to provide 0.56 g ofthe title compound as an oil. MS (ESI/NH₃) m/z 246 (M+H)⁺.

EXAMPLE 270C1-(2,3-dichlorophenyl)-N-({2-[(3aR,7aS)-octahydro-2H-4,7-epoxyisoindol-2-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

The compound from Example 270B (0.19 g) was subjected to reactionconditions according to the method of Example 209 to provide 0.15 g ofthe title compound. MS (ESI/NH₃) m/z 455 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.4-1.6 (m, 4H), 2.4-2.55 (m, 2H), 2.81-2.9 (m, 2H), 4.23-4.3 (d, 2H),4.42-4.5 (m, 2H), 6.8-6.85 (m, 1H), 7.43-7.49 (d, 1H), 7.55-7.61 (t, 2),7.7-7.76 (d, 1H), 7.95-7.99 (d, 1H), 8.05-8.1 (d, 1H).

EXAMPLE 2711-(2,3-dichlorophenyl)-N-(7,8-dimethoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-2-yl)-1H-tetrazol-5-amine

The procedure from Example 209 was followed, substituting7,8-dimethoxy-1,2,3,4-tetrahydro-1,4-methano-naphthalen-2-ylamine (0.19g) (prepared using the procedure as described in Journal of MedicinalChemistry, (1982), 25(4), 363-8) for cyclohexylmethylamine, to give 0.1g of the title compound as a solid. MS (ESI/NH₃) m/z 432 (M+H)⁺; ¹H NMR(δ, DMSO-d₆) 1.62-1.84 (m, 4H), 3.2-3.24 (m, 1H), 3.6 (s, 1H), 3.62-3.65(1H), 3.7 (s, 3H), 3.85 (s, 3H), 6.65-6.7 (d, 1H), 6.81-6.86 (d, 1H),7.17-7.23 (d, 1H), 7.58-7.65 (t, 1H), 7.69-7.73 (d, 1H), 7.95-7.99 (d,1H).

EXAMPLE 2721-(2,3-dichlorophenyl)-N-[(5-methoxy-2,3-dihydro-1H-inden-1-yl)methyl]-1H-tetrazol-5-amine

The procedure from Example 209 was followed, substitutingC-(5-methoxy-indan-1-yl)-methylamine (prepared using the procedure asdescribed in Journal of Pharmacology and Experimental Therapeutics(2004), 308(2), 679-687) (0.16 g) for cyclohexylmethylamine, to give0.12 g of the title compound as a solid. MS (ESI/NH₃) m/z 389 (M+H)⁺; ¹HNMR (δ, DMSO-d₆) 1.7-1.82 (m, 1H), 2.07-2.2 (m, 1H), 2.63-2.85 (m, 2H),3.12-3.3 (m, 1H), 3.3-3.41 (m, 1H), 3.45-3.59 (m, 1H), 3.65 (s, 3H),3.62-3.66 (d, 1H), 6.8 (s, 1H), 7.04-7.13 (d, 1H), 7.26-7.34 (t, 1H),7.58-7.7 (m, 2H), 7.95-7.99 (d, 1H).

EXAMPLE 2731-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)indan-4-ol

The procedure from Example 209 was followed, substituting1-aminomethyl-indan-4-ol (0.088 g) (prepared according to method asdescribed in Journal of Medicinal Chemistry, (1985), 28(10), 1398-404)for cyclohexylmethylamine, to give 0.07 g of the title compound as asolid. MS (ESI/NH₃) m/z 375 (M+H)⁺; ¹H N (δ, DMSO-d₆) 1.7-1.82 (m, 1H),2.07-2.2 (m, 1H), 2.63-2.85 (m, 2H), 3.12-3.3 (m, 1H), 3.3-3.41 (m, 1H),3.45-3.59 (m, 1H), 3.62-3.66 (d, 1H), 6.5-6.6 (d, 1H), 6.9-6.99 (t, 1H),7.26-7.34 (t, 1H), 7.58-7.7 (m, 2H), 7.95-7.99 (d, 1H), 9.16 (s, 1H).

EXAMPLE 2741-(2,3-dichlorophenyl)-N-[(6,7-dimethoxy-2,3-dihydro-1H-inden-1-yl)methyl]-1H-tetrazol-5-amine

The procedure from Example 209 was followed, substitutingC-(6,7-dimethoxy-indan-1-yl)-methylamine (0.188 g) (prepared accordingto method as described in Journal of Medicinal Chemistry, (1985),28(10), 1398-404) for cyclohexylmethylamine, to give 0.15 g of the titlecompound as a solid. MS (ESI/NH₃) m/z 419 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.7-1.82 (m, 1H), 2.07-2.2 (m, 1H), 2.63-2.85 (m, 2H), 3.12-3.3 (m, 1H),3.3-3.41 (m, 1H), 3.45-3.59 (m, 1H), 3.65 (s, 3H), 3.71 (s, 3H),3.62-3.66 (d, 1H), 6.71-6.8 (d, 2H), 6.82-6.88 (d, 2H), 7.26-7.34 (t,1H), 7.58-7.7 (m, 2H), 7.95-7.99 (d, 1H).

EXAMPLE 2751-(2,3-dichlorophenyl)-N-[(4-methoxy-2,3-dihydro-1H-inden-1-yl)methyl]-1H-tetrazol-5-amine

The procedure from Example 209 was followed, substitutingC-(4-methoxy-indan-1-yl)-methylamine (0.16 g) (prepared according to themethod as described in Journal of Medicinal Chemistry, (1985), 28(10),1398-404) for cyclohexylmethylamine, to give 0.086 g of the titlecompound as a solid. MS (ESI/NH₃) m/z 389 (M+H)⁺; ¹H NMR (δ, DMSO-d₆)1.7-1.82 (m, 1H), 2.07-2.2 (m, 1H), 2.63-2.85 (m, 2H), 3.12-3.3 (m, 1H),3.3-3.41 (m, 1H), 3.45-3.59 (m, 1H), 3.65 (s, 3H), 3.71 (s, 3H),3.62-3.66 (d, 1H), 6.71-6.8 (d, 2H), 6.82-6.88 (d, 2H), 7.02-7.12 (t,1H), 7.26-7.34 (t, 1H), 7.58-7.7 (m, 2H), 7.95-7.99 (d, 1H).

EXAMPLE 2761-(2,3-dichlorophenyl)-N-[4-(3-fluoropiperidin-1-yl)-2,3-dihydro-1H-inden-1-yl]-1H-tetrazol-5-amine

The procedure from Example 209 was followed, substituting4-(3-fluoro-piperidin-1-yl)-indan-1-ylamine, to give 0.115 g of thetitle compound as a solid. MS (ESI/NH₃) m/z 446 (M+H)⁺; ¹H NMR (δ,DMSO-d₆) 1.5-1.99 (m, 6H), 2.6-3.1 (m, 6H), 4.59-4.85 (m, 1H), 5.2-5.39(q, 1H), 6.71-6.8 (d, 2H), 6.82-6.88 (d, 2H), 7.02-7.12 (t, 1H),7.4-7.48 (d, 1H), 7.53-7.6 (t, 1H), 7.68-7.72 (d, 1H), 7.93-7.97 (d,1H).

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar was added the isothiocyanate (1.0 eq) and anhydroustetrahydrofuran (15 mL). The flask was sealed with a septum and purgedwith nitrogen. A solution of amine (2.0 eq) in anhydrous tetrahydrofuran(4 mL) was added via syringe. The solution was stirred at roomtemperature overnight. Saturated aqueous sodium bicarbonate (30 mL) wasadded to quench. The mixture was transferred to a separatory funnel andextracted with dichloromethane (3×30 mL). The combined organic extractswere dried over anhydrous magnesium sulfate, filtered, and concentratedby rotary evaporator to give a tan solid. The product was recrystallizedfrom ethyl acetate/heptane to give the thiourea.

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar were added the thiourea (1.0 eq) and sodium azide (3.0eq). The flask was sealed with a septum and purged with a nitrogenatmosphere. Anhydrous tetrahydrofuran (15 mL) was added via syringe.Triethylamine (3.4 eq) was added via syringe. The solid mercury(II)chloride (1.25 eq) was added in one portion and the flask was resealed.A thick, white precipitate formed immediately upon addition of themercury salt. The mixture was stirred at room temperature overnight andmonitored by LC-MS. Ethyl acetate (20 mL) was added, and the solids wereremoved by vacuum filtration through a glass frit. The solids werewashed with ethyl acetate. The liquor was transferred to a separatoryfunnel and washed with water (30 mL). The organic phase was dried overmagnesium sulfate, filtered, and concentrated in vacuo to give anoff-white solid. The crude solid was purified by flash columnchromatography (ISCO Combiflash) on a 40 g silica gel cartridge using30% isocratic for one minutes, then 30%-100% ethyl acetate over 6 min,40 mL/minute. The solvent was removed in vacuo to give the tetrazole.

To an oven-dried, N₂-purged, 250-mL, round-bottomed flask containing amagnetic stir bar were added the commercially available2-chloro-3-cyanopyridine (1.5 eq), the arylboronic acid or ester (1.0eq), and dichlorobis(triphenylphosphine)palladium(II) (0.05 eq). Theflask was sealed with a septum and purged with N₂ atmosphere. Anhydrousdioxane (15 mL) and a N₂-sparged solution of cesium carbonate (3.0 eq)in water (15 mL) were added via syringe. The reaction mixture was heatedto ˜90° C. in an oil bath and stirred for 2 hours. The reaction wasmonitored by LC-MS. After cooling to room temperature, thesolvent/volatiles were removed in vacuo to give a thick brown oil. Water(25 mL) was added and the mixture was transferred to a separatoryfunnel. The mixture was extracted with ethyl acetate (4×10 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated by rotary evaporator to give a brown solid. The crudesolid was purified by flash column chromatography (ISCO Combiflash) on a120 g silica gel cartridge using 30% isocratic for one minutes, then30%-100% ethyl acetate over 6 min, 50 mL/minute. The solvent was removedin vacuo to give the 2-aryl-nicotinonitrile.

To an argon-purged, thick-walled pressure vessel was added wet Raneynickel (˜500 mg). A solution of ammonia-saturated methanol (30 mL) wasadded, followed by the 2-aryl-nicotinonitrile (150 mmol) The vessel wasinserted into a Parr shaker and was charged with 60 psi of H₂ gas. Themixture was shaken at room temperature under static H₂ pressure for 3hours. The H₂ gas was vented and the vessel was purged with argon. Thesolids were removed by vacuum filtration through Celite® 545. Thesolvent/volatiles were removed by rotary evaporator to give the crudeamine.

To an oven-dried, N₂-purged, 25-mL, round-bottomed flask containing amagnetic stir bar was added the arylisothiocyanate (1.0 eq) andanhydrous tetrahydrofuran (10 mL). The flask was sealed with a septumand purged with N₂ atmosphere. A solution of the crude amine (1.2 eq) inanhydrous tetrahydrofuran (2 mL) was added via syringe. The solution wasstirred at room temperature overnight. Saturated aqueous sodiumbicarbonate (10 mL) was added to quench. The mixture was transferred toa separatory funnel and extracted with dichloromethane (3×10 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated by rotary evaporator to give a tan solid. The productwas purified by recrystallization from ethyl acetate/heptane,trituration with dichloromethane or flash column chromatography to givethe thio urea.

To a scintillation vial was added a solution of 0.16 MC-(6′-fluoro-[2,3′]bipyridinyl-3-yl)-methylamine in tetrahydrofuran (3mL, 0.492 mmol) and arylisothiocyanate (0.117 g, 0.492 mmol). The vialwas shaken 1 hour at room temperature. Sodium azide (0.096 g, 1.48 mmol)and triethylamine (0.26 mL, 1.85 mmol) were added, followed by asolution of 0.62 M mercury (II) chloride in tetrahydrofuran (1 mL, 0.625mmol). A thick, white precipitate formed immediately upon addition ofthe mercury salt. The mixture was stirred at room temperature overnightand monitored by LC-MS. Ethyl acetate (5 mL) was added, and the solidswere removed by vacuum filtration through a glass frit. The solvent wasremoved in vacuo and the residue was purified by flash columnchromatography (ISCO Combiflash) on a 12 g silica gel cartridge using10% isocratic for one minutes, then 10%-100% ethyl acetate over 6 min,25 mL/minute. The solvent was removed in vacuo to give the tetrazole.

A mixture of(2-Chloro-pyridin-3-ylmethyl)-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine(100 mg, 0.267 mmol), aryl boronic acid or ester (0.267 mmol),tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) and sodiumcarbonate (71 mg, 0.669 mmol) in dioxane (4 mL) and water (1 mL) wasmicrowaved at 120° C. for 45 minutes. The solid was removed byfiltration and the filtrate was concentrated. The residue was purifiedby flash column chromatography on silica using ethylacetate/dichloromethane (50:50) mixture as the mobile phase to give thecoupled product.

EXAMPLE 277[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-amineEXAMPLE 277A1-(2,3-Dichloro-phenyl)-3-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-thiourea

The title compound was synthesized by general procedure 1 using2,3-dichlorophenylisothiocyanate andC-(6′-fluoro-[2,3′]bipyridinyl-3-yl)-methylamine (Example 192F) to give0.974 g (72%) of1-(2,3-dichloro-phenyl)-3-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-thioureaas a white powder. ¹H NMR (DMSO-d₆, 400 MHz)

4.74 (d, J=4.1 Hz, 2H), 7.31 (dd, J=2.5, J=8.2 Hz, 1H), 7.35 (t, J=8.2Hz, 1H), 7.49 (dd, J=4.7 Hz, J=7.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.87(dd, J=1.5 Hz, J=7.9 Hz, 1H), 8.17 (dt, J=2.5 Hz, J=8.2 Hz, 1H), 8.39(bs, 1H), 8.41 (d, J=2.5 Hz, 1H) 8.60 (dd, J=1.6 Hz, J=4.7 Hz, 1H), 9.49(bs, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm; 5%-100%acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min), then 100%acetonitrile isocratic 2 minutes, R_(t) 10.30 min. (94.3%); MS: M+H⁺407.

EXAMPLE 277B[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-amine

The title compound was prepared from the product of Example 277A usingGeneral Procedure 2. ¹H NMR (DMSO-d₆, 400 MHz)

4.53 (d, J=5.3 Hz, 2H), 7.32 (dd, J=2.7 Hz, J=8.5 Hz, 1H), 7.47 (dd,J=4.8 Hz, J=7.8 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.68 (dd, J=1.4 Hz,J=7.9 Hz, 1H), 7.75 (t, J=5.4 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.95 (d,J=8.0 Hz, 1H), 8.23 (dt, J=2.4 Hz, J=8.2 Hz, 1H), 8.45 (d, J=2.4 Hz,1H), 8.60 (t, J=4.8 Hz, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25cm; 5%-100% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min),then 100% acetonitrile isocratic 2 minutes, R_(t) 9.95 min. (>99.5%);MS: M+H⁺ 415, 417.

EXAMPLE 278[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl](2′-fluoro-[2,4′]bipyridinyl-3-ylmethyl)amineEXAMPLE 278A 2-(1H-Pyrazol-4-yl)-nicotinonitrile

The title compound was synthesized from 2-fluoropyridine-4-boronic acidusing General Procedure 3. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.66 (m, 1H),7.77 (dd, J=4.9 Hz, J=8.0 Hz, 1H), 7.84 (ddd, J=1.4 Hz, J=2.0 Hz, J=5.2Hz, 1H), 8.49 (td, J=0.7 Hz, J=5.2 Hz, 1H), 8.55 (dd, J=1.7 Hz, J=8.0Hz, 1H), 9.02 (dd, J=1.7 Hz, J=4.9 Hz, 1H); RP-HPLC (Hypersil® HS C18, 5μm, 100 Å, 25 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 10min, 1 mL/min), then 100% acetonitrile isocratic 2 minutes, R_(t) 9.10min. (96.6%).

EXAMPLE 278B1-(2,3-Dichloro-4-fluorophenyl)-3-(2′-fluoro-[2,4′]bipyridinyl-3-ylmethyl)thiourea

The title compound was prepared from the product of Example 278A and2,3-dichloro-4-fluorophenylisothiocyanate using General Procedure 4. ¹HNMR (DMSO-d₆, 400 MHz)

4.74 (m, 2H), 7.31-7.38 (m, 1H), 7.39-7.59 (m, 4H), 7.88 (d, J=6.8 Hz,1H), 8.19-8.39 (m, 1H), 8.36 (d, J=4.1 Hz, 1H), 8.55-8.73 (m, 1H),9.44-9.64 (bs, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm;5%-100% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min), then100% acetonitrile isocratic 2 minutes, R_(t) 10.40 min. (95.3%); MS: MH⁺424.

EXAMPLE 278C[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl](2′-fluoro-[2,4′]bipyridinyl-3-ylmethyl)amine

The title compound was prepared using General Procedure 2 from theproduct of Example 278B. ¹H NMR (DMSO-d₆, 400 MHz) δ 1H-NMR (400 MHz) δ4.55 (d, J=5.5 Hz, 2H), 7.39-7.42 (m, 1H), 7.51 (dd, J=4.7 Hz, J=7.9 Hz,1H), 7.57 (ddd, J=1.4 Hz, J=2.1 Hz, J=5.1 Hz, 1H), 7.68 (t, J=5.6 Hz,1H), 7.74 (t, J=8.8 Hz, 1H), 7.80 (dd, J=5.4 Hz, J=9.0 Hz, 1H), 7.93(dd, J=1.6 Hz, J=7.9 Hz, 1H), 8.36 (d, J=5.1 Hz, 1H), 8.62 (dd, J=1.6Hz, J=4.7 Hz, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm;50%-100% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min), then100% acetonitrile isocratic 2 minutes, R_(t) 5.50 min. (99.6%), MS: MH⁺434.

EXAMPLE 279[2-(1-Benzyl-1H-pyrazol-4-yl)pyridin-3-ylmethyl]-[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amineEXAMPLE 279A 2-(1-Benzyl-1H-pyrazol-4-yl)-nicotinonitrile

The title compound was prepared from1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleusing General Procedure 3. ¹H NMR (DMSO-d₆, 400 MHz) δ 5.46 (s, 2H),7.30-7.38 (m, 5H), 7.41 (dd, J=4.9 Hz, J=7.9 Hz, 1H), 8.21 (s, 1H), 8.30(dd, J=1.8 Hz, J=7.9 Hz, 1H), 8.62 (s, 1H), 8.80 (dd, J=1.7 Hz, J=4.8Hz, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm; 50%-100%acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min), then 100%acetonitrile isocratic 2 minutes, R_(t) 5.95 min. (99.0%), MS: M+H⁺ 261.

EXAMPLE 279B1-[2-(1-Benzyl-1H-pyrazol-4-yl)-pyridin-3-ylmethyl]-3-(2,3-dichloro-4-fluorophenyl)thiourea

The title compound was prepared from the product of Example 279A usingGeneral Procedure 4. ¹H NMR (DMSO-d₆, 400 MHz)

4.90 (d, J=3.5 Hz, 2H), 5.46 (s, 2H), 7.29-7.45 (m, 6H), 7.52 (t, J=8.9Hz, 1H), 7.60-7.68 (m, 1H), 7.75 (dd, J=1.6 Hz, J=7.8 Hz, 1H), 8.01 (s,1H), 8.37-8.45 (m, 2H), 8.53 (s, 1H), 9.62 (s, 1H); RP-HPLC (Hypersil®HS C18, 5 μm, 100 Å, 25 cm; 50%-100% acetonitrile-0.1M ammonium acetateover 10 min, 1 mL/min), then 100% acetonitrile isocratic 2 minutes,R_(t) 7.01 min. (99.4%); MS: M+H⁺ 487.

EXAMPLE 279C[2-(1-Benzyl-1H-pyrazol-4-yl)pyridin-3-ylmethyl]-[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amine

The title compound was prepared from the product of Example 279B usingGeneral Procedure 4. ¹H NMR (DMSO-d₆, 400 MHz) δ 4.64 (d, J=5.2 Hz, 2H),5.39 (s, 1H), 7.23 (s, 1H), 7.27-7.39 (m, 5H), 7.69-7.77 (m, 3H), 7.86(dd, J=5.3 Hz, J=9.0 Hz, 1H), 7.94 (d, J=0.7 Hz, 1H), 8.32 (d, J=0.7 Hz,1H), 8.47 (dd, J=1.7 Hz, J=4.7 Hz, 1H); RP-HPLC (Hypersil® HS C18, 5 μm,100 Å, 25 cm; 50%-100% acetonitrile-0.1M ammonium acetate over 10 min, 1mL/min), then 100% acetonitrile isocratic 2 minutes, R_(t) 6.54 min.(99.5%); MS: M+H⁺ 496.

EXAMPLE 280[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl](2-methylpyridin-3-ylmethyl)amineEXAMPLE 280A1-(2,3-Dichloro-4-fluorophenyl)-3-(2-methylpyridin-3-ylmethyl)thiourea

The title compound was prepared from2,3-dichloro-4-fluorophenylisothiocyanate andC-(2-methylpyridin-3-yl)methylamine using General Procedure 1. ¹H NMR(DMSO-d₆, 400 MHz)

2.47 (s, 3H), 4.69 (m, 2H), 7.21 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 7.46 (t,1H, J=8.9 Hz), 7.54-7.67 (bs, 1H), 7.58 (dd, 1H, J=1.4 Hz, J=7.7 Hz),8.26-8.42 (bs, 1H), 8.33 (dd, 1H, J=1.7 Hz, J=4.8 Hz), 9.49 (s, 1H);RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100%acetonitrile-0.1M ammonium acetate over 5 min, 2 mL/min), then 100%acetonitrile isocratic 1 minutes, R_(t) 3.69 min. (90.8%); MS: M+H⁻ 342.

EXAMPLE 280B[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl](2-methylpyridin-3-ylmethyl)amine

The title compound was prepared from the product of Example 280A usingGeneral Procedure 2. ¹H NMR (DMSO-d₆, 400 MHz)

2.49 (s, 3H), 4.49 (d, J=5.5 Hz, 2H), 7.19 (dd, J=4.8 Hz, J=7.7 Hz, 1H),7.58-7.65 (m, 2H), 7.75 (t, J=8.8 Hz, 1H), 7.89 (dd, J=5.3 Hz, J=9.0 Hz,1H), 8.34 (dd, J=1.7 Hz, J=4.8 Hz, 1H); RP-HPLC (Hypersil®-100 C18, 5μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 5 min,2 mL/min), then 100% acetonitrile isocratic 1 minutes, R_(t) 3.62 min.(95.1%); MS: M+H⁺ 353.

EXAMPLE 281[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]-(5,6,7,8-tetrahydroquinolin-5-yl)amineEXAMPLE 281A 1-(2,3-Dichloro-4-fluorophenyl)-3-(5,6,7,8-tetrahydroquinolin-5-yl)thiourea

The title compound was prepared from2,3-dichloro-4-fluorophenylisothiocyanate and5,6,7,8-tetrahydroquinolin-5-ylamine using General Procedure 1. ¹H NMR(DMSO-d₆, 400 MHz)

1.77-1.93 (m, 2H), 1.93-2.12 (m, 2H), 2.81-2.97 (m, 2H), 5.70-5.83 (m,1H), 7.28 (dd, 1H, J=4.7 Hz, J=7.8 Hz), 7.51 (t, 1H, J=8.9 Hz),7.62-7.78 (m, 2H), 8.37 (d, 1H, J=8.5 Hz), 8.43 (dd, 1H, J=1.4 Hz, J=4.5Hz), 9.39 (s, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm;5%-100% acetonitrile-0.1M ammonium acetate over 5 min, 2 mL/min), then100% acetonitrile isocratic 1 minutes, R_(t) min. (98.9%); MS: M+H⁺ 370.

EXAMPLE 281B[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]-(5,6,7,8-tetrahydroquinolin-5-yl)amine

The title compound was prepared from the product of Example 281A usingGeneral Procedure 2. ¹H NMR (DMSO-d₆, 400 MHz)

1.74-2.08 (m, 4H), 2.74-2.89 (m, 2H), 4.96-5.07 (m, 1H), 7.19 (dd, J=4.7Hz, J=7.8 Hz. 1H), 7.49 (d, J=8.4 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.70(t, J=8.8 Hz, 1H), 7.85 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.37 (dd, J=1.3Hz, J=4.7 Hz, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm;5%-100% acetonitrile-0.1M ammonium acetate over 5 min, 2 mL/min), then100% acetonitrile isocratic 1 minutes, R_(t) 3.84 min. (98.3%); MS: M+H⁺379.

EXAMPLE 282[1-(4-Chloro-3-trifluoromethylphenyl)-1H-tetrazol-5-yl](6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)amine

The title compound was synthesized from4-chloro-3-(trifluoromethyl)phenyl isothiocyanate using Generalprocedure 5. ¹H NMR (DMSO-d₆, 400 MHz) δ 4.90 (s, 2H), 7.31 (dt, J=2.7Hz, J=8.2 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.53 (dd, J=4.7 Hz, J=7.8 Hz,1H), 7.65 (d, J=8.6 Hz, 1H), 8.08 (dd, J=1.7 Hz, J=7.8 Hz, 1H), 8.21 (m,1H), 8.45 (d, J=2.6 Hz, 1H), 8.67 (dd, J=1.7 Hz, J=4.8 Hz, 1H); RP-HPLC(Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1Mammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic1 minutes, R_(t) 5.30 min. (97.5%); MS: M+H⁺ 448, 450.

EXAMPLE 2841′-Benzyl-3-{[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-1′H-[2,4′]bipyridinyl-2′-oneEXAMPLE 284A1′-Benzyl-2′-oxo-1′,2′-dihydro-[2,4′]bipyridinyl-3-carbonitrile

The title compound was prepared from1-Benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-oneusing General Procedure 3. ¹H-NMR (400 MHz DMSO-d₆) δ 5.18 (s, 2H), 6.65(dd, J=2.1 Hz, J=7.1 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 7.36 (m, 5H), 7.70(dd, J=4.9 Hz, J=8.0 Hz, 1H), 8.00 (dd, J=0.5 Hz, J=7.1 Hz, 1H), 8.48(dd, J=1.7 Hz, J=7.9 Hz, 1H), 8.95 (dd, J=1.7 Hz, J=4.9 Hz, 1H).

EXAMPLE 284B1-(1′-Benzyl-2′-oxo-1′,2′-dihydro-[2,4′]bipyridinyl-3-ylmethyl)-3-(2,3-dichloro-4-fluoro-phenyl)-thiourea

The title compound was prepared from1′-benzyl-2′-oxo-1′,2′-dihydro-[2,4′]bipyridinyl-3-carbonitrile usingGeneral Procedure 4. MS (ESI⁺) m/z 513.3 (M+H)⁺; R_(t)=1.91 min. ¹H-NMR(400 MHz DMSO-d₆) δ4.75 (s, 2H), 5.17 (s, 2H), 6.41 (dd, J=1.5 Hz, J=6.9Hz, 1H), 6.51 (s, 1H), 7.34 (m, 4H), 7.46 (m, 2H), 7.54 (m, 1H), 7.89(d, J=7.0 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 8.31 (s, 1H), 8.55 (d, J=4.0Hz, 1H), 9.57 (s, 1H).

EXAMPLE 284C1′-Benzyl-3-{[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-1′H-[2,4′]bipyridinyl-2′-one

The title compound was prepared by from the product of Example 284Busing General Procedure 2. MS (ESI⁺) m/z 521.9 (M+H)⁺; Rt=1.91 min;¹H-NMR (400 MHz, DMSO-d₆) δ 4.55 (d, J=5.43 Hz, 2H), 5.15 (s, 2H), 5.57(d, J=1.7 Hz, 1H), 6.44 (dd, J=1.9 Hz, J=7.0 Hz, 1H), 7.36 (m, 5H), 7.45(dd, J=4.7 Hz, J=7.9 Hz, 1H), 7.69 (m, 1H), 7.72 (m, 1H), 7.80 (dd, 1H,J=5.35 Hz, J=8.99 Hz), 7.87 (m, 2H), 8.56 (dd, J=1.6 Hz, J=4.7 Hz, 1H).

EXAMPLE 285(2-Chloro-pyridin-3-ylmethyl)-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amineEXAMPLE 285A1-(2-Chloropyridin-3-ylmethyl)-3-(2,3-dichloro-4-fluorophenyl)thiourea

The title compound was prepared from2,3-dichloro-1-fluorophenylisothiocyanate andC-(2-Chloro-pyridin-3-yl)-methylamine using General Procedure 1. MS(ESI⁺) m/z 364.1 (M+H)⁺; R_(t)=2.08 min. ¹H-NMR (400 MHz DMSO-d₆) δ 4.74(s, 2H), 7.48 (m, 2H), 7.74 (dd, J=1.75, 7.62 Hz, 1H), 8.32 (dd, J=1.89,4.72 Hz, 1H), 8.37 (s, 1H), 9.70 (s, 1H).

EXAMPLE 285B(2-Chloro-pyridin-3-ylmethyl)-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine

The title compound was prepared from the product of Example 285B usingGeneral Procedure 2. MS (ESI⁺) m/z 373.2 (M+H)⁺; R_(t)=1.96 min. ¹H-NMR(400 MHz, DMSO-d₆) δ 4.55 (d, J=5.6 Hz, 1H), 7.44 (dd, J=4.7 Hz, J=7.6Hz, 1H), 7.80 (m, 3H), 7.92 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.34 (dd,J=1.9 Hz, J=4.7 Hz, 1H).

EXAMPLE 2884-(3-{[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-ylamino]methyll}pyridin-2-yl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester EXAMPLE 288A4-(2-Cyano-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester

2-Chloro-nicotinonitrile (1.0 g, 7.215 mmol) was added to a mixture of[1,4]Diazepane-1-carboxylic acid tert-butyl ester and potassiumhydrogencarbonate (0.87 g, 8.66 mmol) in N,N-dimethylformamide (20 mL).The mixture was heated at 90° C. overnight. The reaction mixture waspoured onto ice and extracted with dichloromethane. The organic layerwas washed with water and brine then dried over magnesium sulfate andfiltered. The solvent was removed and the residue was purified by flashcolumn chromatography on silica using ethyl acetate/heptane (50:50)mixture as the mobile phase to give4-(2-Cyano-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester.¹H-NMR (400 MHz, DMSO-d₆) δ 1.25 (d, 27 Hz, 9H), 1.81 (m, 1H), 1.87 (m,1H), 3.31 (m, 2H), 3.55 (m, 1H), 3.60 (m, 1H), 3.84 (m, 2H), 3.94 (m,2H), 6.75 (m, 2H), 8.34 (m, 1H).

EXAMPLE 288B4-{3-[3-(2,3-Dichloro-4-fluoro-phenyl)-thioureidomethyl]-pyridin-2-yl}-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was prepared from the product of Example 288A, and2,3-dichloro-4-fluorophenylisothiocyanate using General Procedure 4. MS(ESI⁺) m/z 512.9 (M+H)⁺; R_(t)=1.96. ¹H NMR (DMSO-d₆) δ 1.38 (d, J=15.0Hz, 9H), 1.85 (m, 2H), 3.29 (m, 2H), 3.39 (m, 4H), 3.52 (m, 2H), 4.66(s, 2H), 6.93 (dd, J=4.9 Hz, J=7.2 Hz, 1H), 7.54 (d, 1H, J=6.8 Hz, 7.46(t, J=8.9 Hz, 1H), 7.58 (m, 1H), 8.11 (dd, J=1.7 Hz, J=4.7 Hz, 1H), 8.23(s, 1H), 9.51 (s, 1H).

EXAMPLE 288C4-(3-{[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-ylamino]methyl}pyridin-2-yl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was prepared from4-{3-[3-(2,3-Dichloro-4-fluoro-phenyl)-thioureidomethyl]-pyridin-2-yl}-[1,4]diazepane-1-carboxylicacid tert-butyl using General Procedure 2. MS (ESI⁺) m/z 536.9 (M+H)⁺;R_(t)=2.35 min. ¹H-NMR (400 MHz, DMSO-d₆) δ 1.37 (d, J=14.4 Hz, 9H),1.84 (m, 2H), 3.29 (m, 2H), 3.38 (m, 4H), 3.52 (m 2H), 4.45 (d, J=4.7Hz, 1H), 6.91 (dd, J=4.8 Hz, J=7.5 Hz, 1H), 7.56 (dd, J=1.8 Hz, J=7.5Hz, 1H), 7.61 (m, 1H), 7.74 (t, J=8.8 Hz, 1H), 7.87 (dd, J=5.3 Hz, J=9.0Hz, 1H), 8.11 (dd, J=1.9 Hz, J=4.8 Hz, 1H).

EXAMPLE 289(2-[1,4]Diazepan-1-yl-pyridin-3-ylmethyl)-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine,diacetate salt

Trifluoroacetic acid (3 mL) was added to a solution of the product ofExample 288C (0.40 g, 0.744 mmol) in dichloromethane (15 mL) at 0° C. 5minutes later, the ice bath was removed and the reaction mixture wasstirred at room temperature for 16 hours. The solvent was removed andthe residue was purified by preparative HPLC on a Thermoquest, hyperprepHS C18 column (250×21.2 mm., 8 μm particle size) using a gradient of 5%to 75% acetonitrile to ammonium acetate (10 mM) over 20 minutes at aflow rate of 21 mL/min to provide the title compound. MS (ESI⁺) m/z437.3 (M+H)⁺; R_(t)=1.41 min. ¹H-NMR (400 MHz, DMSO-d₆) δ 1.78 (m, 2H),1.98 (s, 6H), 2.84 (m, 2H), 2.90 (m, 2H), 3.38 (m, 4H), 4.46 (d, J=5.1Hz, 2H), 6.85 (dd, J=4.8 Hz, J=7.5 Hz, 1H), 7.53 (dd, J=1.9 Hz, J=7.5Hz, 1H), 7.61 (t, J=5.6 Hz, 1H), 7.74 (t, J=8.8 Hz, 1H), 7.86 (dd, J=5.3Hz, J=9.0 Hz, 1H), 8.08 (dd, J=1.9 Hz, J=4.8 Hz, 1H).

EXAMPLE 290[1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-[2-(4-isopropyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-aminediacetate salt

Acetone (0.5 mL) was added to a mixture of the product of Example 289(80 mg, 0.183 mmol) and sodium triacetoxyborohydride (77 mg, 0.366 mmol)in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at roomtemperature overnight. The mixture was filtered and washed withdichloromethane. The filtrate was concentrated under reduced pressureand purified by preparative HPLC on a Thermoquest, hyperprep HS C18column (250×21.2 mm., 8 μm particle size) using a gradient of 5% to 75%acetonitrile to ammonium acetate (10 mM) over 20 minutes at a flow rateof 21 mL/min to provide the title compound. MS (ESI⁺) m/z 479.3 (M+H)⁺;R_(t)=1.63 min. ¹H-NMR (400 MHz, DMSO-d₆) δ 0.96 (d, J=6.6 Hz, 1H), 1.80(m, 2H), 1.90 (s, 2H), 2.65 (m, 2H), 2.70 (m, 2H), 2.86 (m, 1H), 3.38(m, 4H), 4.44 (d, J=5.3 Hz, 1H), 5.75 (s, 1H), 6.84 (dd, J=4.8 Hz, J=7.5Hz, 1H), 7.52 (dd, J=1.9 Hz, J=7.5 Hz, 1H), 7.58 (t, J=5.5 Hz, 1H), 7.73(t, J=8.8 Hz, 1H), 7.86 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.07 (dd, J=1.9Hz, J=4.7 Hz, 1H).

To a solution of amine (A) (80 mg, 0.183 mmol) in dimethylformamide (2ml) was added potassium carbonate (51 mg, 0.366 mmol) and alkylbromide(B) (0.220 mmol). The reaction mixture was stirred at room temperaturefor 16 hours then poured onto ice water. The aqueous mixture wasextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated. The residue waspurified by flash column chromatography or preparative HPLC on aThermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size)using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM)over 20 minutes at a flow rate of 21 mL/min to provide the titlecompound.

To a solution of amine (A) (80 mg, 0.183 mmol) in dichloromethane (3 ml)was added triethylamine (0.2 mL) and acylating reagent (C) (0.366 mmol).The reaction mixture was stirred at room temperature for 2 hours.Saturated sodium carbonate was added and the layers were separated. Theaqueous mixture was extracted with dichloromethane. The organic layerwas washed with brine, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography orpreparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2 mm,8 μm particle size) using a gradient of 5% to 75% acetonitrile toammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min toprovide the title compound.

To an oven-dried, N₂-purged, 50-mL, round-bottomed flask containing amagnetic stir bar were added the commercially available2-fluoro-3-cyanopyridine (216 mg, 1.77 mmol), the arylhydroxide (D)(1.77 mmol), anhydrous potassium carbonate (318 mg, 2.30 mmol) andanhydrous acetonitrile (10 mL). The reaction mixture was stirred for 18hours at ambient temperature. The insoluble material was removed byfiltration and the solvent was removed from the filtrate in vacuo togive the 2-aryloxy-nicotinonitrile.

Examples 291-298 in Table 1 were prepared from the appropriate aldehydesor ketones using the procedure as described in Example 290.

TABLE 1 Name MH⁺ Rt Exam- [1-(2,3-Dichloro-4-fluoro-phenyl)-1H- 493.31.77 ple 291 tetrazol-5-yl]-[2-(4-isobutyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine Exam- [2-(4-Cyclopropylmethyl-[1,4]diazepan-1-491.4 1.59 ple 292 yl)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine Exam-[1-(2,3-Dichloro-4-fluoro-phenyl)-1H- 507.4 1.89 ple 293tetrazol-5-yl]-{2-[4-(2,2-dimethyl-propyl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine Exam-[1-(2,3-Dichloro-4-fluoro-phenyl)-1H- 479.3 1.63 ple 294tetrazol-5-yl]-[2-(4-propyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine Exam- [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-533.3 1.75 ple 295 tetrazol-5-yl]-{2-[4-(3,3,3-trifluoro-propyl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine Exam-[1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5- 535.4 1.48 ple 296yl]-{2-[4-(tetrahydro-pyran-4-ylmethyl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine Exam-[2-(4-Cyclopentyl-[1,4]diazepan-1-yl)-pyridin-3- 505.4 1.73 ple 297ylmethyl]-[1-(2,3-dichloro-4-fluoro-phenyl)-1H- tetrazol-5-yl]-amineExam- [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5- 521.4 1.49 ple298 yl]-{2-[4-(tetrahydro-pyran-4-yl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine

EXAMPLE 2991-(2,3-dichlorophenyl)-N-[(2,4-dimethylpyridin-3-yl)methyl]-1H-tetrazol-5-amine

C-(2,4-dimethyl-pyridin-3-yl)-methylamine (Lu et al Bioorg. Med. Chem.Lett. Vol. 13, page 1821-1824, 2003)) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI+) m/z 349 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.33 (s, 3H) 2.51 (s, 3H) 4.51 (d, J=4.60 Hz, 2H)7.05 (d, J=4.91 Hz, 1H) 7.28 (t, J=4.76 Hz, 1H) 7.57 (t, J=7.98 Hz, 1H)7.67 (dd, J=8.00, 1.53 Hz, 1H) 7.90 (dd, J=8.13, 1.38 Hz, 1H)

EXAMPLE 3001-(2,3-dichlorophenyl)-N-(quinolin-8-ylmethyl)-1H-tetrazol-5-amine

C-quinolin-8-yl-methylamine (WO 2001070229) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI+) m/z 372 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 5.15 (d, J=5.83 Hz, 2H) 7.55-7.61 (m, 2H) 7.62 (t,J=8.29 Hz, 1H) 7.68 (dd, J=7.21, 1.38 Hz, 1H) 7.72-7.75 (m, 1H) 7.77(dd, J=8.00, 1.53 Hz, 1H) 7.90 (dd, J=7.98, 1.23 Hz, 1H) 7.94 (dd,J=8.13, 1.38 Hz, 1H) 8.39 (dd, J=8.29, 1.84 Hz, 1H) 8.94 (dd, J=4.30,1.84 Hz, 1H)

EXAMPLE 3011-(2,3-dichlorophenyl)-N-[2-(4-methylphenoxy)benzyl]-1H-tetrazol-5-amine

2-p-Tolyloxy-benzylamine (US 2002143003) was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI+) m/z 426 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.29 (s, 3H) 4.51 (d, 5.76 Hz, 2H) 6.80 (dd, J=8.14,1.02 Hz, 1H) 6.86 (d, J=8.48 Hz, 2H) 7.07-7.14 (m, 1H) 7.18 (d, J=8.14Hz, 2H) 7.21-7.29 (m, 1H) 7.39 (dd, J=7.63, 1.53 Hz, 1H) 7.56-7.68 (m,3H) 7.94 (dd, J=7.80, 2.03 Hz, 1H)

EXAMPLE 3021-(2,3-dichlorophenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]-1H-tetrazol-5-amine

(R)-1-(3-methoxyphenyl)ethylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI+) m/z 364 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.43 (d, J=7.12 Hz, 3H) 3.73 (s, 3H) 4.82-4.93 (m,1H) 6.76-6.81 (m, 1H) 6.89-6.95 (m, 2H) 7.22 (t, J=8.14 Hz, 1H) 7.56 (d,J=7.80 Hz, 1H) 7.62 (t, J=7.80 Hz, 1H) 7.67 (dd, J=6.00, 2.03 Hz, 1H)7.96 (dd, J=7.97, 1.86 Hz, 1H).

EXAMPLE 3031-(2,3-dichlorophenyl)-N-[(1S)-1-(3-methoxyphenyl)ethyl]-1H-tetrazol-5-amine

(S)-1-(3-methoxyphenyl)ethylamine was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (ESI+) m/z 364 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.43 (d, J=7.12 Hz, 3H) 3.73 (s, 3H) 4.81-4.94 (r,1H) 6.75-6.82 (m, 1H) 6.89-6.95 (m, 2H) 7.22 (t, J=8.14 Hz, 1H) 7.56 (d,J=8.14 Hz, 1H) 7.62 (t, J=7.80 Hz, 1H) 7.68 (dd, J=9.00, 2.03 Hz, 1H)7.96 (dd, J=7.97, 1.86 Hz, 1H)

EXAMPLE 3041-(2,3-dichlorophenyl)-N-{2-[(1-methylpiperidin-3-yl)oxy]benzyl}-1H-tetrazol-5-amineEXAMPLE 304A 2-[(1-methylpiperidin-3-yl)oxy]benzonitrile

2-Fluoro-benzonitrile was reacted with 1-methyl-piperidin-3-ol accordingto the method of Example 85A to provide the title compound. MS (DCI/NH₃)m/z 217 (M+1)⁺.

EXAMPLE 304B 1-{2-[(1-methylpiperidin-3-yl)oxy]phenyl}methanamine

The product from Example 304A according to the method of Example 78Bprovided the title compound. MS (DCI/NH₃) m/z 221 (M+1)⁺.

EXAMPLE 304C1-(2,3-dichlorophenyl)-N-{2-[(1-methylpiperidin-3-yl)oxy]benzyl}-1H-tetrazol-5-amine

The product from Example 304B was reacted with2,3-dichlorophenylisothiocyanate according to the method of Example 78Cto provide the title compound. MS (DCI/NH₃) m/z 434 (M+1)⁺, ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.99-1.10 (m, 1H) 1.37-1.49 (m, 1H) 1.53-1.62 (m,1H) 1.70-1.84 (m, 3H) 2.02 (s, 3H) 2.39-2.47 (m, 1H) 2.62 (d, J=8.54 Hz,1H) 4.31-4.39 (m, 1H) 5.48 (s, 2H) 6.95 (t, J=7.48 Hz, 1H) 7.06 (d,J=8.24 Hz, 1H) 7.25-7.33 (m, 2H) 7.34-7.37 (m, 2H) 7.70 (dd, J=6.26,3.51 Hz, 1H) 8.58-9.26 (br.s, 1H).

EXAMPLE 3051-(2,3-dichloro-4-fluorophenyl)-N-[(2-{4-[(dimethylamino)acetyl]-1,4-diazepan-1-yl}pyridin-3-yl)methyl]-1H-tetrazol-5-aminediacetate

Prepared according to General Procedure 8 using Example 289 anddimethylaminoacetyl chloride hydrochloride. MS (ESI⁺) m/z 522.3 (M+H);R_(t) 1.34 min.

EXAMPLE 3074-[3-({[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-N,N-dimethyl-1,4-diazepane-1-sulfonamide

Prepared according to General Procedure 8 using Example 289 anddimethylsulfamoylchloride. MS (ESI⁺) m/z 544.3 (M+H); R_(t) 2.08 min.

EXAMPLE 3081-(2,3-dichloro-4-fluorophenyl)-N-({2-[4-(methylsulfonyl)-1,4-diazepan-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine

Prepared according to General Procedure 8 using Example 289 andmethanesulfonylchloride. MS (ESI⁺) m/z 515.3 (M+H); R_(t) 1.94 min.

EXAMPLE 309 ethyl{4-[3-({[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,4-diazepan-1-yl}acetate

Prepared according to General Procedure 7 using Example 289 andethylchloroacetate. MS (ESI⁺) m/z 523.3 (M+H); R_(t) 1.76 min.

EXAMPLE 310N-{[2-(4-acetyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amine

Prepared according to General Procedure 8 using Example 289 andacetylchloride. MS (ESI⁺) m/z 479.3 (M+H); R_(t) 1.70 min.

EXAMPLE 3112-{4-[3-({[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,4-diazepan-1-yl}acetamideacetate

Prepared according to General Procedure 7 using Example 289 and2-chloroacetamide. MS (ESI⁺) m/z 494.4 (M+H); R_(t) 1.43 min.

EXAMPLE 312[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl][2-(6-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]amineEXAMPLE 312A 2-(6-Fluoropyridin-3-yloxy)nicotinonitrile

The title compound was synthesized according to General Procedure 9using 2-fluoro-5-hydroxypyridine. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.33 (dd,1H, J=3.3 Hz, J=8.8 Hz), 7.37 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 8.01 (ddd,1H, J=3.0 Hz, J=6.7 Hz, J=8.9 Hz), 8.26 (dd, 1H, J=1.6 Hz, J=2.9 Hz),8.40 (dd, 1H, J=1.9 Hz, J=5.0 Hz), 8.47 (dd, 1H, J=1.9 Hz, J=7.6 Hz);RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100%acetonitrile-0.1M ammonium acetate over 5 min. 2 mL/min), then 100%acetonitrile isocratic 1 minutes, R_(t) 3.67 min.

EXAMPLE 312B1-(2,3-Dichloro-4-fluorophenyl)-3-[2-(6-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]thiourea

The title compound was prepared from Example 313A and Example 192D usingGeneral Procedure 4.

EXAMPLE 312C[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl][2-(6-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]amine

The title compound was prepared from Example 312B using GeneralProcedure 2. ¹H NMR (DMSO-d₆, 400 MHz) δ 4.62 (d, 2H, J=5.4 Hz), 7.16(dd, 1H, J=4.9 Hz, J=7.4 Hz), 7.27 (dd, 1H, J=3.3 Hz, J=8.8 Hz),7.71-7.78 (m, 1H), 7.81 (dd, 1H, J=1.8 Hz, J=7.4 Hz), 7.85 (ddd, 1H,J=3.0 Hz, J=6.8 Hz, J=8.9 Hz), 7.27 (dd, 1H, J=3.3 Hz, J=8.8 Hz), 7.76(t, 1H, J=8.8 Hz), 7.91 (dd, 1H, J=5.3 Hz, J=9.0 Hz), 8.02 (dd, 1H,J=1.9 Hz, J=4.9 Hz), 8.11 (dd, 1H, J=1.5 Hz, J=2.9 Hz); RP-HPLC(Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1Mammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic1 minutes, R_(t) 4.37 min; MS: MH⁺ 450.

EXAMPLE 313[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-Yl][2-(2-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]amineEXAMPLE 313A 2-(2-Fluoropyridin-3-yloxy)nicotinonitrile

The title compound was synthesized by General Procedure 9 using2-fluoro-3-hydroxypyridine. ¹H NMR (DMSO-d₆. 400 MHz) δ 7.41 (dd, 1H,J=5.0 Hz, J=7.6 Hz), 7.51 (ddd, 1H, J=1.1 Hz, J=4.9 Hz, J=7.8 Hz), 8.09(ddd, 1H, J=1.7 Hz, J=7.8 Hz, J=9.7 Hz), 8.19 (td, 1H, J=1.6 Hz, J=4.9Hz), 8.42 (dd, 1H, J=1.9 Hz, J=5.0 Hz), 8.50 (dd, 1H, J=1.9 Hz, J=7.6Hz); RP-HPLC (Hypersil®1-100 C18, 5 μm, 100 Å, 10 cm; 5%-100%acetonitrile-0.1M ammonium acetate over 5 min. 2 mL/min), then 100%acetonitrile isocratic 1 minutes, R_(t) 3.62 min.

EXAMPLE 313B1-(2,3-Dichloro-4-fluorophenyl)-3-[2-(2-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]thiourea

The title compound was prepared from Example 313A and Example 192D usingGeneral Procedure 4. ¹H NMR (DMSO-d₆, 400 MHz) δ 4.85 (d, 2H, J=5.0 Hz),7.20 (dd, 1H, J=5.0 Hz, J=7.3 Hz), 7.43-7.51 (m, 2H), 7.62 (dd, 1H,J=5.8 Hz, J=8.1 Hz), 7.78 (dd, 1H, J=1.0 Hz, J=7.3 Hz), 7.92 (ddd, 1H,J=1.6 Hz, J=7.8 Hz, J=9.7 Hz), 7.99 (dd, 1H, J=1.7 Hz, J=4.9 Hz), 8.11(td, 1H, J=1.3 Hz, J=4.8 Hz), 8.39 (s, 1H), 9.63 (s, 1H); RP-HPLC(Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1Mammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic1 minutes, R_(t) 3.73 min; MS: MH⁺ 441.

EXAMPLE 313C[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl][2-(2-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]amine

The title compound was prepared from Example 313B using GeneralProcedure 2. ¹H NMR (DMSO-d₆, 400 MHz) δ 4.64 (d, 2H, J=5.6 Hz), 7.18(dd, 1H, J=4.9 Hz, J=7.4 Hz), 7.46 (ddd, 1H, J=0.8 Hz, J=4.8 Hz, J=7.9Hz), 7.73-7.78 (m, 1H), 7.76 (t, 1H, J=8.8 Hz), 7.82 (dd, 1H, J=1.8 Hz,J=7.4 Hz), 7.87-7.93 (m, 2H), 8.01 (dd, 1H, J=1.8 Hz, J=4.9 Hz), 8.11(td, 1H, J=1.5 Hz, J=4.8 Hz); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å,10 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 5 min, 2 mL/min),then 100% acetonitrile isocratic 1 minutes, R_(t) 4.31 min.; MS: MH⁺450.

EXAMPLE 314[1-(2,3-Dichlorophenyl)-1H-tetrazol-5-yl]-[2-(2-fluoropyridin-3-yloxy)-pyridin-3-ylmethyl]amineEXAMPLE 314A1-(2,3-Dichlorophenyl)-3-[2-(2-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]thiourea

The title compound was prepared from Example 313A and2,3-dichlorophenylisothiocyanate using General Procedure 4. ¹H NMR(DMSO-d₆, 400 MHz) δ 4.86 (d, 2H, J=4.2 Hz), 7.20 (dd, 1H, J=4.9 Hz,J=7.3 Hz), 7.36 (t, 1H, J=8.1 Hz), 7.46 (dd, 1H, J=4.9 Hz, J=7.7 Hz),7.53 (dd, 1H, J=1.4 Hz, J=8.1 Hz), 7.64 (d, 1H, J=7.2 Hz), 7.79 (dd, 1H,J=1.8 Hz, J=7.4 Hz), 7.92 (ddd, 1H, J=1.7 Hz, J=7.8 Hz, J=9.7 Hz), 8.00(dd, 1H, J=1.8 Hz, J=4.9 Hz), 8.11 (td, 1H, J=1.4 Hz, J=4.8 Hz), 8.48(s, 1H), 9.61 (s, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm;5%-100% acetonitrile-0.1M ammonium acetate over 5 min. 2 mL/min), then100% acetonitrile isocratic 1 minutes, R_(t) 3.73 min.; MS: MH⁺ 423.

EXAMPLE 314B[1-(2,3-Dichlorophenyl)-1H-tetrazol-5-yl]-[2-(2-fluoropyridin-3-yloxy)-pyridin-3-ylmethyl]amine

The title compound was prepared from Example 314A using GeneralProcedure 2. ¹H NMR (DMSO-d₆, 400 MHz) δ 4.64 (d, 2H, J=5.6 Hz), 7.18(dd, 1H, J=5.0 Hz, J=7.3 Hz), 7.46 (dd, 1H, J=4.8 Hz, J=7.8 Hz), 7.63(dt, 1H, J=0.9 Hz, J=8.2 Hz), 7.73-7.86 (m, 3H), 7.88-7.99 (m, 1H), 7.97(ddd, 1H, J=0.9 Hz, J=1.4 Hz, J=8.2 Hz), 8.01 (dd, 1H, J=1.3 Hz, J=5.0Hz), 8.11 (d, 1H, J=4.8 Hz); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10cm; 5%-100% acetonitrile-0.1M ammonium acetate over 5 min. 2 mL/min),then 100% acetonitrile isocratic 1 minutes, R_(t) 4.28 min.; MS: MH⁺432.

EXAMPLE 3154-(3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-pyridin-2-yl)-piperazine-1-carboxylicacid tert-butyl ester EXAMPLE 315A4-(3-Cyano-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester

2-Chloro-nicotinonitrile (2.04 g, 14.7 mmol) was added to a mixture ofpiperazine-1-carboxylic acid tert-butyl ester (2.74 g, 14.7 mmol) andpotassium hydrogencarbonate (1.77 g, 17.6 mmol) in N,N-dimethylformamide(45 mL). The mixture was heated at 90° C. overnight. The solvent wasremoved and residue was partitioned between ethyl acetate and water. Theorganic layer was washed with water and brine then dried over magnesiumsulfate and filtered. The solvent was removed to give the titledcompound as an oil. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.428 (dd, 1H); 8.08 (dd1H); 6.95 (dd, 1H); 3.58 (m, 4H); 3.47 (m, 4H); 1.42 (s, 9H).

EXAMPLE 315B4-{3-[3-(2,3-Dichloro-phenyl)-thioureidomethyl]-pyridin-2-yl}-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared by General Procedure 4 using Example315A and 2,3-dichloro-phenylisothiocyanate. MS (ESI⁺) m/z 496.4 (M+H)⁺;R_(t)=2.11. ¹H NMR (DMSO-d₆) δ 9.534 (bs, 1H); 8.336 (bs, 1H); 8.207 (m1H); 7.651 (m, 1H); 7.592 (m, 1H); 7.518 (m, 1H); 7.359 (m, 1H); 7.088(m, 1H); 4.747 (m, 2H); 3.468 (m, 4H); 2.988 (m, 4H); 1.423 (s, 9H).

EXAMPLE 315C4-(3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-pyridin-2-yl)-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared by General Procedure 2 using Example315B. MS (ESI⁺) m/z 503.5 (M+H)⁺; R_(t)=2.07 min. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.187 (m, 1H); 7.947 (m, 1H); 7.735 (m, 1H); 7.695 (m, 1H);7.635 (m, 2H); 7.616 (m, 1H); 4.517 (m, 2H); 3.459 (m, 4H); 2.990 (m,4H); 1.425 (s, 9H).

EXAMPLE 316[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(2-piperazin-1-yl-pyridin-3-ylmethyl)amine,acetate salt

Trifluoroacetic acid (45 mL) was added to a solution of Example 315C(5.72 g, 11.32 mmol) in dichloromethane (220 mL) at 0° C. After 5minutes, the ice bath was removed and the reaction mixture was stirredat room temperature for 16 hours. The residue was partitioned betweendichloromethane and 1.0 N sodium hydroxide. The organic solvent wasremoved and the residue was purified by preparative HPLC on aThermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size)using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM)over 20 minutes at a flow rate of 21 mL/min to provide the titlecompound. MS (ESI⁺) m/z 405.4 (M+H)⁺; R_(t)=1.37 min. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.180 (m, 1H); 7.942 (m, 1H); 7.728 (m, 1H); 7.668 (m, 1H);7.612 (m, 2H); 7.000 (m, 1H); 4.498 (m, 2H); 2.961 (m, 4H); 2.842 (m,4H); 1.891 (m, 3H).

The following examples 317-320 were prepared according to the method ofExample 290, substituting Example 263 or Example 316 for Example 289. Inthe case of Examples 318 and 320 propionaldehyde was used instead ofacetone.

EXAMPLE 317[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-isopropyl-piperazin-1-yl)-pyridin-3-ylmethyl]-amine

447.5 (M+H)⁺; R_(t)=1.46

EXAMPLE 318[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-propyl-piperazin-1-yl)-pyridin-3-ylmethyl]-amine

447.5 (M+H)⁺; R_(t)=1.50

EXAMPLE 319[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-isopropyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine

461.5 (M+H)⁺; R_(t)=1.50

EXAMPLE 320[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-propyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine

461.5 (M+H)⁺; R_(t)=1.55

The following examples 321-322 were prepared according to GeneralProcedure 7 using either Example 263 or Example 316 for the aminecomponent (A).

EXAMPLE 3212-[4-(3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-pyridin-2-yl)-[1,4]diazepan-1-yl]-acetamide

476.4 (M+H)⁺; R_(t)=1.38

EXAMPLE 3222-[4-(3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-pyridin-2-yl)-piperazin-1-yl]-acetamide

462.4 (M+H)⁺; R_(t)=1.39

The following compounds encompassed by the present invention may beprepared by one skilled in the art using known synthetic methodologies,the starting materials may be varied and additional steps may beemployed. Alternatively they may be prepared by using syntheticmethodology described in the scheme and examples contained herein, withreadily apparent modifications:

-   1-(2,3-dichlorophenyl)-N-[(2′-fluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′,6′-difluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′,4′,6′-trifluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′,5′-difluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(5′,6′-difluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′,4′-difluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′-fluoro-2,4′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′,6′-difluoro-2,4′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′,5′-difluoro-2,4′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2′,3′-difluoro-2,4′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-({2-[(2,6-difluoropyridin-3-yl)oxy]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-({2-[(6-fluoropyridin-3-yl)oxy]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-({2-[(4,6-difluoropyridin-3-yl)oxy]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-({2-[(2,5-difluoropyridin-3-yl)oxy]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(pyrimidin-5-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(pyridazin-4-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(pyrazin-2-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-pyridazin-4-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-pyrimidin-5-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-pyrazin-2-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(1,3-thiazol-5-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(1,3,4-thiadiazol-2-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(1,3-oxazol-5-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   4-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3H-pyrazol-3-one;-   3-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-pyridine    N-oxide;-   4-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-pyridine    N-oxide;-   3′-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)-2H-1,2′-bipyridin-2-one;-   1-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]pyrimidin-2(1H)-one;-   1-(2,3-dichlorophenyl)-N-{[2-(4H-1,2,4-triazol-4-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   3-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,3,4-oxadiazol-2(3H)-one;-   2-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   1-(2,3-dichlorophenyl)-N-({2-[(6-fluoropyridin-3-yl)sulfonyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-({2-[(5-fluoropyridin-3-yl)sulfonyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-({2-[(4-fluoropyridin-3-yl)sulfonyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-({2-[(2-fluoropyridin-3-yl)sulfonyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(pyrrolidin-3-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)-N-pyrrolidin-3-ylpyridin-2-amine;-   3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)-N-tetrahydrofuran-3-ylpyridin-2-amine;-   N-{[2-(3-aminopyrrolidin-1-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-hexahydropyrrolo[3,2-b]pyrrol-1(2H)-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(hexahydro-1H-pyrrolizin-1-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-piperazin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   N-{[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-{[2-(1,4-diazabicyclo[3.2.2]non-4-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-ethylpyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   N-[(3-chloropyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-methoxypyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[3-(trifluoromethyl)pyridin-4-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-isopropylpyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-fluoropyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-phenoxypyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   4-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)nicotinonitrile;-   1-(2,3-dichlorophenyl)-N-[1-methyl-1-(3-methylpyridin-4-yl)ethyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-morpholin-4-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-5,6,7,8-tetrahydroisoquinolin-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-ethylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   N-[(2-chloropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-methoxypyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-isopropylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(2-phenoxypyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[1-methyl-1-(2-methylpyridin-3-yl)ethyl]-1H-tetrazol-5-amine:-   1-(2,3-dichlorophenyl)-N-[(2-morpholin-4-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(2,6-dimethylmorpholin-4-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(3,5-dimethylmorpholin-4-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-pyrrolidin-1-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-piperidin-1-ylbenzyl)-1H-tetrazol-5-amine;-   N-(2-azetidin-1-ylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-piperazin-1-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(4-methylpiperazin-1-yl)benzyl]-1H-tetrazol-5-amine;-   N-(2-anilinobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{2-[methyl(phenyl)amino]benzyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-pyridin-2-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-pyridin-3-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-pyridin-4-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(4,5-dihydro-1H-imidazol-1-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(1H-imidazol-1-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(1,3-oxazol-2-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(pyrazin-2-yloxy)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(pyridin-3-yloxy)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(imidazo[1,2a]pyridin-8-ylmethyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-methylpyridazin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(4-methylpyrimidin-5-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(3-methylpyrazin-2-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(5-methylpyrimidin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[(5-methylpyridazin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(1,5-naphthyridin-4-ylmethyl)-1H-tetrazol-5-amine;-   N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-2-methylpyridin-3-amine;-   N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]-3-methylpyridin-4-amine;-   1-[2-chloro-3-(trifluoromethyl)phenyl]-N-(2-methylphenyl)-1H-tetrazol-5-amine;-   N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]pyridin-3-amine;-   N-[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]pyridin-4-amine;-   1-(2,3-dichloro-4-fluorophenyl)-N-(2-methylphenyl)-1H-tetrazol-5-amine;-   1-[2-fluoro-3-(trifluoromethyl)phenyl]-N-(2-methylphenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-5-(2-phenylpyrrolidin-1-yl)-1H-tetrazole;-   1-(2,3-dichlorophenyl)-N-{2-[2-(dimethylamino)ethoxy]benzyl}-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-{2-[(dimethylamino)methyl]benzyl}-1H-tetrazol-5-amine;-   N-[5-chloro-2-(trifluoromethyl)benzyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-(2-chloro-6-fluoro-3-methylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-(2-chloro-3,6-difluorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2,3,6-trifluorobenzyl)-1H-tetrazol-5-amine;-   N-(6-chloro-2-fluoro-3-methylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-(5-chloro-2-fluorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(5-fluoro-2-methylbenzyl)-1H-tetrazol-5-amine;-   N-[2-chloro-5-(trifluoromethyl)benzyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[5-fluoro-2-(trifluoromethyl)benzyl]-1H-tetrazol-5-amine;-   N-(5-chloro-2-methylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(trifluoromethyl)benzyl]-1H-tetrazol-5-amine;-   N-(3-chloro-2-fluorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2,5-difluorobenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(difluoromethoxy)benzyl]-1H-tetrazol-5-amine;-   N-(2,5-dichlorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-(2,3-dichlorobenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylbenzyl)-1H-tetrazol-5-amine:-   1-(2,3-dichlorophenyl)-N-[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-octahydro-2H-4,7-epoxyisoindol-2-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)benzyl]-1H-tetrazol-5-amine;-   N-[2-(2-azabicyclo[2.2.1]hept-2-yl)benzyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)benzyl]-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-[2-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)benzyl]-1H-tetrazol-5-amine;-   N-(3-chloro-2-morpholin-4-ylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-(4-chloro-2-morpholin-4-ylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-(5-chloro-2-morpholin-4-ylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   N-(2-chloro-6-morpholin-4-ylbenzyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(2-fluoro-6-morpholin-4-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(3-fluoro-2-morpholin-4-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(4-fluoro-2-morpholin-4-ylbenzyl)-1H-tetrazol-5-amine;-   1-(2,3-dichlorophenyl)-N-(5-fluoro-2-morpholin-4-ylbenzyl)-1H-tetrazol-5-amine;-   N-[(3-chloropyridin-4-yl)methyl]-1-[2-chloro-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-amine;-   N-[(3-chloropyridin-4-yl)methyl]-1-[2-fluoro-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-amine;-   1-[2-chloro-3-(trifluoromethyl)phenyl]-N-[(3-methylpyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-[2-fluoro-3-(trifluoromethyl)phenyl]-N-[(3-methylpyridin-4-yl)methyl]-1H-tetrazol-5-amine;-   1-[2-chloro-3-(trifluoromethyl)phenyl]-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine;    and-   1-[2-fluoro-3-(trifluoromethyl)phenyl]-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine.

The foregoing detailed description and accompanying examples are merelyillustrative and are not intended to limit the invention to thedisclosed compounds. Various changes and modifications to the disclosedembodiments will be apparent to those skilled in the art. Such changesand modifications, including without limitation those relating to thechemical structures, substituents, derivatives, intermediates,syntheses, formulations and/or methods of use of the invention, may bemade without departing from the spirit and scope of the invention whichare defined in the appended claim.

1. A compound having Formula (I),

or a therapeutically acceptable salt thereof, in which R² is phenyl, in which each R² is substituted with one, two, three, four, or five substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a); R^(2a) is —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or R^(2b); R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —Br, —I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂, —NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c); R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; m is 1; X and Y is —H; or X and Y together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dioxolane, tetrahydropyran, piperidine, morpholine, thiomorpholine, and piperazine, each or which is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a)) ₂, —CN, —SR^(2a), and —SO₂R^(2a); Z is —H; or Z and X together with the atoms to which they are attached form a ring selected from the group consisting of pyrrolidine, piperidine, morpholine, thiomorpholine, and piperazine; R¹ is pyridyl, which is unfused or fused with a ring selected from the group consisting of cyclopentane, cyclohexane, cyclopentene, cyclohexene, naphthalene, benzene, furan, imidazole, isothiazole, oxazole, isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, tetrahydrofuran, tetrahydrothiophene, thiazole, thiophene, pyrrolidine, dioxolane, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, and piperazine wherein each ring is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of of —Cl, —F, —Br, —I, —OH, —NH₂, —NO₂, —R^(1a), —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂, —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e))—NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1b); R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d); R^(1c) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, in which each R^(1c) is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —NH₂, —OR^(1aa), —SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂, —C(O)R^(1aa), —S(O)₂R^(1aa), —S(O)₂NH₂, —S(O)₂N(R^(1aa))₂, —C(O)NH₂, —C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h), —N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h); R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1bb); R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h); R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; R^(1e) is a monocyclic or bicyclic ring selected from the group consisting of cycloalkyl, heterocycle, aryl and heteroaryl, wherein each ring is unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂, —NHR^(1aa), and —N(R^(1aa))₂; R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, aryl, heteroaryl, —R^(1h), or R^(1g); R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one substituent selected from the group consisting —R^(1h); R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, in which each R^(1h) is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂.
 2. A compound having Formula (I),

or a therapeutically acceptable salt thereof, in which R² is phenyl, wherein each R² is substituted with one, two, three, four, or five substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a); R^(2a) is —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or R^(2b); R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —Br, —I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂, —NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c); R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; m is 1; X and Y is —H; or X and Y together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dioxolane, tetrahydropyran, piperidine, morpholine, thiomorpholine, and piperazine, each or which is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a); Z is —H; or Z and X together with the atoms to which they are attached form a ring selected from the group consisting of pyrrolidine, piperidine, morpholine, thiomorpholine, and piperazine; R¹ is pyridyl which is unfused or fused with a ring selected from the group consisting of cyclopentane, cyclohexane, cyclopentene, cyclohexene, naphthalene, benzene, furan, imidazole, isothiazole, oxazole, isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, tetrahydrofuran, tetrahydrothiophene, thiazole, thiophene, pyrrolidine, dioxolane, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, and piperazine, wherein each ring is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1a), —OR^(1a)—NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂—SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂, —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1b); R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d); R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl, imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl, tetrahydrofuryl, tetrahydrothienyl thiazolyl, thienyl, pyrrolidinyl, dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl, 1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, ═O, —NO₂, —CN, —OH, —R^(1aa), —NH₂, —OR^(1aa), —SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂, —C(O)R^(1aa), S(O)₂R^(1aa), S(O)₂NH₂, S(O)₂N(R^(1aa))₂, —C(O)NH₂, —C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h), —N(H)R^(1b)), —N(R^(1d))(R^(1h)) and R^(1h); R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1bb); R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d); —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h); R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl, azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein each R^(1e) is unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂, —NHR^(1aa), and —N(R^(1aa))₂; R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, aryl, heteroaryl, —R^(1h), or R^(1g); R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one substituent selected from the group consisting of aryl and heteroaryl; R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, in which each R^(1h) is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂.
 3. The compound of claim 1 having Formula (I),

or a therapeutically acceptable salt thereof, in which R² is phenyl, in which each R² is substituted with one, two, three, four, or five substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a); R^(2a) is —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or R^(2b); R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —Br, —I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂, —NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c); R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; m is 1; X and Y is H; or X and Y together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dioxolane, tetrahydropyran, piperidine, morpholine, thiomorpholine, and piperazine, each of which is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a); Z is —H; or Z and X together with the atoms to which they are attached form a ring selected from the group consisting of pyrrolidine, piperidine, morpholine, thiomorpholine, and piperazine; R¹ is pyridyl which is unfused or fused with a ring selected from the group consisting of cyclopentane, cyclohexane, cyclopentene, cyclohexene, naphthalene, benzene, furan, imidazole, isothiazole, oxazole, isoxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, tetrahydrofuran, tetrahydrothiophene, thiazole, thiophene, pyrrolidine, dioxolane, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, and piperazine, wherein each ring is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂, —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1b); R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d); R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl, imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl, tetrahydrofuryl, tetrahydrothienyl thiazolyl, thienyl, pyrrolidinyl, dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl, 1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —NH₂, —OR^(1aa), —SR^(1aa), —NHR^(1aa), —N(R^(1aa))₂, —C(O)R^(1aa), —S(O)₂R^(1aa), —S(O)₂NH₂, —S(O)₂N(R^(1aa))₂, —C(O)NH₂, —C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h), —N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h); R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1bb); R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h); R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl, azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein each R^(1e) is unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂, —NHR^(1aa), and —N(R^(1aa))₂; R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, aryl, heteroaryl, —R^(1h), or R^(1g); R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one substituent selected from the group consisting of R^(1h); R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, in which each R^(1h) is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂.
 4. The compound of claim 3, or a therapeutically acceptable salt thereof, in which R² is phenyl substituted with one, two, three, four, or five substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a); R^(2a) is —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or R^(2b); R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —Br, —I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂, —NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c); R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, R¹ is pyridyl which is unfused or fused with a ring selected from the group consisting of cyclopentane, cyclohexane, cyclopentene, cyclohexene and a benzene, wherein each ring is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NO₂, —OH, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂, —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1b); R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d); R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl, imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl, tetrahydrofuryl, tetrahydrothienyl thiazolyl, thienyl, pyrrolidinyl, dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl, 1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —SR^(1aa), —NH₂, —OR^(1aa), —NHR^(1aa), —N(R^(1aa))₂ —C(O)R^(1aa), —S(O)₂R^(1aa), —S(O)₂NH₂, —S(O)₂N(R^(1aa))₂, —C(O)NH₂, —C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h), —N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h); R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1bb); R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d) —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h); R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl, azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein each R^(1e) is unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂, —NHR^(1aa), and —N(R^(1aa))₂; R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, aryl, heteroaryl, —R^(1h), or R^(1g); and R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one substituent selected from the group consisting of —R^(1h), R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, in which each R^(1h) is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂.
 5. The compound of claim 3, or a therapeutically acceptable salt thereof, in which R² is phenyl substituted with one, two, three, four, or five substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —NH₂, —R^(2a), —OR^(2a), —NHR^(2a), —NHR^(2a), —N(R^(2a))₂, —CN, —SR^(2a), and —SO₂R^(2a); R^(2a) is —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or R^(2b); R^(2b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —Br, —I, —F, —Cl, —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —NH₂, —NHR^(2c), —N(R^(2c))₂, —CN, —SR^(2c), and —SO₂R^(2c); R^(2c) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, R¹ is pyridyl, which is unfused and unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of —Cl, —F, —Br, —I, —OH, —NO₂, —NH₂, —R^(1a), —OR^(1a), —NHR^(1a), —N(R^(1a))₂, —CN, —SR^(1a), —SO₂R^(1a), —SO₂NH₂, —SO₂N(H)(R^(1a)), —SO₂N(R^(1a))₂, —C(O)R^(1a), —C(O)OH, —C(O)OR^(1a), —C(O)NH₂, —C(O)N(H)(R^(1a)), —C(O)N(R^(1a))₂, —OR^(1e), —SR^(1e), —SO₂R^(1e), —SO₂N(H)(R^(1e)), —SO₂N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NH(R^(1e)), —N(R^(1d))(R^(1e)), —NHC(O)R^(1f), —N(R^(1d))C(O)R^(1f), and —R^(1c); R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1b); R^(1b) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NH₂, —OH, —OR^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —R^(1c), —N(R^(1d))₂, and —NHR^(1d); R^(1c) is cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, naphthyl, quinolinyl, isoquinolinyl, phenyl, furyl, imidazolyl, isothiazolyl, oxazolyl, oxazolinyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolinyl, tetrahydrofuryl, tetrahydrothienyl thiazolyl, thienyl, pyrrolidinyl, dioxolanyl, pyrazolinyl, pyrazolidinyl, pyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, octahydro-1H-4,7-methanoisoindolyl, octahydro-1H-4,7-epoxyisoindolyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 1,4-diazepanyl, 1,4-diazabicyclo[3.2.2]nonyl, 1,4-diazatricyclo[4.3.1.1^(3,8)]undecyl, 3,10-diazabicyclo[4.3.1]decyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, each of which is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —SR^(1aa), —NH₂, —OR^(1aa), —NHR^(1aa), —N(R^(1aa))₂ —C(O)R^(1aa), —S(O)₂R^(1aa), —S(O)₂NH₂, —S(O)₂N(R^(1aa))₂, —C(O)NH₂, —C(O)N(H)(R^(1aa)), —C(O)N(R^(1aa))₂, —C(O)OH, —C(O)OR^(1aa), —OR^(1h), —N(H)R^(1h)), —N(R^(1d))(R^(1h)) and —R^(1h); R^(1aa) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, or —R^(1bb); R^(1bb) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one or two or three substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d) —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), —S(O)₂N(R^(1d))₂ and —R^(1h); R^(1d) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; R^(1e) is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolidinyl, piperidyl, azepinyl, tetrahydrofuryl, tetrahydropyranyl or oxazolyl; wherein each R^(1e) is unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of ═O, —Cl, —F, —Br, —I, —NO₂, —CN, —OH, —R^(1aa), —OR^(1aa), —SR^(1aa), —NH₂, —NHR^(1aa), and —N(R^(1aa))₂; R^(1f) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, aryl, heteroaryl, —R^(1h), or R^(1g); R^(1g) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl, each of which is substituted with one substituent selected from the group consisting of R^(1h); and R^(1h) is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, in which each R^(1h) is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —NO₂, —CN, haloalkyl, haloalkoxy, —NH₂, —OH, —OR^(1d), —SR^(1d), —S(O)₂R^(1d), —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, —C₆-alkyl, —N(R^(1d))₂, —NHR^(1d), —C(O)OH, —C(O)OR^(1d), —C(O)NH₂, —C(O)N(H)(R^(1d)), —C(O)N(R^(1d))₂, —S(O)₂NH₂, —S(O)₂N(H)(R^(1d)), and —S(O)₂N(R^(1d))₂.
 6. The compound of claim 3, or a therapeutically acceptable salt thereof, in which R² is phenyl substituted with two substituents independently selected from the group consisting of —Cl, —F, —Br, —I and R^(2a); R^(2a) is —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl, or —C₆-alkyl; m is 1; X and Y is —H; Z is —H; R¹ is (a) unfused pyridyl, unsubstituted or substituted with one —R^(1a) substituent; or (b) pyridyl fused with a distal cyclopentane, cyclohexane, or benzene, wherein each ring is unsubstituted or substituted with one —R^(1a) substituent; and R^(1a) is —C₁-alkyl, —C₂-alkyl, —C₃-alkyl, —C₄-alkyl, —C₅-alkyl or —C₆-alkyl.
 7. The compound of claim 3, or a therapeutically acceptable salt thereof, in which R² is phenyl substituted with two substituents independently selected from the group consisting of —Cl and —C₁-alkyl; m is 1; X and Y is —H; Z is H; and R¹ is (a) unfused pyridyl, unsubstituted or substituted with one —C₁-alkyl substituent; or (b) pyridyl fused with a ring selected from the group consisting of cyclopentane, cyclohexane, or benzene, wherein each ring is unsubstituted or substituted with one —C₁-alkyl substituent.
 8. The compound of claim 3, or a therapeutically acceptable salt thereof, selected from the group consisting of: 1-(2,3-dichlorophenyl)-N-(pyridin-4-ylmethyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-(pyridin-3-ylmethyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-(quinolin-4-ylmethyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(3-methylpyridin-4-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylmethyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-(5,6,7,8-tetrahydroquinolin-3-ylmethyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-methylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-phenoxypyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-methoxypyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-(quinolin-3-ylmethyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[(6-methylpyridin-3-yl)oxy]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; N-({6-chloro-5-fluoro-2-[(1-methylpyrrolidin-3-yl)oxy]pyridin-3-yl}methyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-(pyridin-2-ylmethyl)-1H-tetrazol-5-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-4-yloxy)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-piperidin-3-yloxy)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(1-methyl-pyrrolidin-3-yloxy)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(2-methyl-pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine; [2-(5-Chloro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[6-methyl-2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(5-fluoro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine; [2-(2-Chloro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine; [2-(6-Chloro-5-fluoro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine; [6-Chloro-5-fluoro-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(6-fluoro-2-methyl-pyridin-3-ylmethyl)-amine; 1-(2,3-dichlorophenyl)-N-[(2-morpholin-4-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-ethylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine; N-[(2-chloro-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(3-fluoropyridin-4-yl)methyl]-1H-tetrazol-5-amine; N-[(3-chloropyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-[2-fluoro-3-(trifluoromethyl)phenyl]-N-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichloro-4-fluorophenyl)-N-{[2-(pyridin-3-yloxy)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; N-[(2-chloropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; N-[(2-bromopyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-fluoropyridin-4-yl)methyl]-1H-tetrazol-5-amine; N-[(2-bromopyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-phenylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(4-ethoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(4-methylphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; N-{[2-(4-chlorophenyl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; N-{[2-(3-chlorophenyl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(3-methylphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(3,4-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2-methylphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; N-{[2-(2-chlorophenyl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2-phenoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[2-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-thien-2-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-thien-3-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; N-(2,3′-bipyridin-3-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; N-(2,4′-bipyridin-3-ylmethyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(1,3-thiazol-2-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[5-fluoro-2-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2-methoxyphenyl)-6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2-fluoro-6-methoxyphenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2,4-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2,3-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2,5-difluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2,4,6-trifluorophenyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-piperidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; N-[(2-azetidin-1-ylpyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(5-fluoro-2-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; N-benzyl-3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-amine; 1-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; N-[(2-chloro-3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; N-[(2-azetidin-1-yl-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2,5-difluoro-6-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-[(2-phenyl-3-pyrrolidin-1-ylpyridin-4-yl)methyl]-1H-tetrazol-5-amine; N-[(2-azepan-1-ylpyridin-3-yl)methyl]-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-pyrrolidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; N-benzyl-3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)-N-methylpyridin-2-amine; 1-(2,3-dichloro-4-fluorophenyl)-N-[(6′-fluoro-2,3′-bipyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-[2-chloro-4-fluoro-3-(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-[4-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine; N-[(2-fluoropyridin-3-yl)methyl]-1-(2,3,4-trichlorophenyl)-1H-tetrazol-5-amine; N-[(2-fluoropyridin-3-yl)methyl]-1-(2,3,5-trichlorophenyl)-1H-tetrazol-5-amine; 1-[2,3-bis(trifluoromethyl)phenyl]-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichloro-4-fluorophenyl)-N-[(2-fluoropyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichloro-4-fluorophenyl)-N-[(2-thien-3-ylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; N-[(2-azetidin-1-yl-5-fluoropyridin-3-yl)methyl]-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichloro-4-fluorophenyl)-N-{[2-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; N-(2,3′-bipyridin-3-ylmethyl)-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; N-{[2-(3-azabicyclo[3.2.2]non-3-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[4-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(3-fluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(4-fluoropiperidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; 1-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]pyrrolidin-3-ol; 1-(2,3-dichlorophenyl)-N-{[2-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2-methylpyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(1,4-oxazepan-4-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-{[2-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1H-tetrazol-5-amine; tert-butyl 4-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,4-diazepane-1-carboxylate; N-{[2-(1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; tert-butyl 3-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate; N-{[2-(3,6-diazabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]methyl}-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; benzyl (1S,5S)-6-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate; N-({2-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]pyridin-3-yl}methyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; benzyl (1R,5R)-6-[3-({[1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate; N-({2-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-6-yl]pyridin-3-yl}methyl)-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichlorophenyl)-N-({2-[(3aR,7aS)-octahydro-2H-4,7-epoxyisoindol-2-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-amine; [1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl](2′-fluoro-[2,4′]bipyridinyl-3-ylmethyl)amine; [2-(1-Benzyl-1H-pyrazol-4-yl)pyridin-3-ylmethyl]-[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amine; [1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl](2-methylpyridin-3-ylmethyl)amine; [1-(4-Chloro-3-trifluoromethylphenyl)-1H-tetrazol-5-yl](6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)amine; 3-{5-[(6′-Fluoro-[2,3′]bipyridinyl-3-ylmethyl)amino]tetrazol-1-yl}benzonitrile; 1′-Benzyl-3-{[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-1′H-[2,4′]bipyridinyl-2′-one; (2-Chloro-pyridin-3-ylmethyl)-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-(2′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl](2-pyrimidin-5-yl-pyridin-3-ylmethyl)amine; 4-(3-{[1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-ylamino]methyl}pyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester; (2-[1,4]Diazepan-1-yl-pyridin-3-ylmethyl)-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-[2-(4-isopropyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-[2-(4-isobutyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine; [2-(4-Cyclopropylmethyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-{2-[4-(2,2-dimethyl-propyl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-[2-(4-propyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-{2-[4-(3,3,3-trifluoro-propyl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-{2-[4-(tetrahydro-pyran-4-ylmethyl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine; [2-(4-Cyclopentyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-[1-(2,3-dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-amine; [1-(2,3-Dichloro-4-fluoro-phenyl)-1H-tetrazol-5-yl]-{2-[4-(tetrahydro-pyran-4-yl)-[1,4]diazepan-1-yl]-pyridin-3-ylmethyl}-amine; 1-(2,3-dichlorophenyl)-N-[(2,4-dimethylpyridin-3-yl)methyl]-1H-tetrazol-5-amine; 1-(2,3-dichloro-4-fluorophenyl)-N-({2-[4-(methylsulfonyl)-1,4-diazepan-1-yl]pyridin-3-yl}methyl)-1H-tetrazol-5-amine; ethyl {4-[3-({[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,4-diazepan-1-yl}acetate; N-{[2-(4-acetyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-amine; 1-(2,3-dichloro-4-fluorophenyl)-N-[(2-{4-[(dimethylamino)acetyl]-1,4-diazepan-1-yl}pyridin-3-yl)methyl]-1H-tetrazol-5-amine; 4-[3-({[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-N,N-dimethyl-1,4-diazepane-1-sulfonamide; [1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl][2-(6-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]amine; [1-(2,3-Dichloro-4-fluorophenyl)-1H-tetrazol-5-yl][2-(2-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]amine; [1-(2,3-Dichlorophenyl)-1H-tetrazol-5-yl]-[2-(2-fluoropyridin-3-yloxy)pyridin-3-ylmethyl]amine; 4-(3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-(2-piperazin-1-yl-pyridin-3-ylmethyl)amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-isopropyl-piperazin-1-yl)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-propyl-piperazin-1-yl)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-isopropyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine; [1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-yl]-[2-(4-propyl-[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-amine; 2-[4-(3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-pyridin-2-yl)-[1,4]diazepan-1-yl]-acetamide; 2-[4-(3-{[1-(2,3-Dichloro-phenyl)-1H-tetrazol-5-ylamino]-methyl}-pyridin-2-yl)-piperazin-1-yl]-acetamide; and 2-{4-[3-({[1-(2,3-dichloro-4-fluorophenyl)-1H-tetrazol-5-yl]amino}methyl)pyridin-2-yl]-1,4-diazepan-1-yl}acetamide.
 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2, or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 10. A method for treating chronic inflammatory pain or neuropathic pain comprising administering to a patient in need of such treatment a pharmaceutical composition of claim
 9. 11. A method for treating chronic inflammatory pain or neuropathic pain comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or 2, or a therapeutically acceptable salt thereof.
 12. A method for inhibiting P2X₇ activity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or 2, or a therapeutically acceptable salt thereof.
 13. A method for treating inflammation and inflammatory pain comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or 2, or a therapeutically acceptable salt thereof. 